JP6969800B2 - Substituted 2,4-diamino-quinoline derivatives used to treat proliferative disorders - Google Patents

Description

The present invention relates to novel substituted 2,4-amino-quinoline derivatives, their manufacture, pharmaceutical compositions containing them, and their use as pharmaceuticals.
The novel substituted 2,4-amino-quinoline derivatives of the present invention are useful in the treatment of proliferative disorders, including cancer.
The present invention relates generally to the field of treating proliferative disorders, especially cancer.

Cancer is a disease characterized by the disorderly proliferation and diffusion of abnormal cells. These abnormal cells can form a swelling mass, spread to important organs, and eventually cause the patient's death. Cancer affects people all over the world.

Traditional approaches to the treatment of abnormal cell proliferation include surgery, chemotherapy, radiation therapy, etc., as well as combinations thereof. Surgery is not always an option, depending on the size or location of the tumor and / or advanced metastases. In addition, surgery may not completely remove neoplastic tissue. Radiation therapy can often cause serious side effects. Chemotherapy typically involves the use of one or more compounds that inhibit cancer cell proliferation. The best known anti-cancer agents are unfortunately narrowly selective for cancer and are basically toxic to both cancerous and normal tissues. They can also cause serious side effects such as hair loss, suppression of hematopoiesis, and nausea. Depending on the patient's general health, these side effects can interfere with the administration of chemotherapeutic agents, or at least are extremely unpleasant and unpleasant for the patient, significantly degrading the remaining quality of life of the cancer patient. Decrease.

The discovery of new anti-cancer agents has recently shifted from cell-based assays to a more focused in vitro approach to finely characterized, isolated, and transfection-assisted expressed drug candidate proteins. The shift from cytotoxic chemotherapy to the discovery and development of molecularly targeted anti-cancer agents is increasing the number of successful treatments, which is impacting the lives of many cancer patients. The ABL inhibitor imatinib is generally the most conceptual in the design of small molecular therapies to treat a well-defined patient population (in this case, patients with chronic myelogenous leukemia that progresses with the BCR-ABL translocation). Considered an impressively proven pioneering drug, its survival improvement was dramatic (Druker, S. et al., N. Engl. J. Med. 2006 (355) 2408-2417). .. However, despite significant advances made in new targeted therapies, some cancers appear to have natural resistance to clinical use of kinase inhibitors, or molecular targeted therapies do. Is not appropriate (eg, hepatocellular carcinoma and pancreatic cancer). Moreover, a molecular understanding and explanation of the progression of cell transformation, cancer growth, cancer microenvironment, and metastasis is still evolving, for example, with respect to the concept of cancer stem cells (CSCs) or tumor-initiating cells (TICs).

In 2013, the estimated number of liver cancers is 559,000 for men and 233,000 for women, including dominant hepatocellular carcinoma (HCC), hepatoblastoma, and sarcoma. The estimated deaths from this tumor were 554,000 and 254,000, respectively. Globally, liver cancer is the second most common cancer in men and the fifth most common cancer in females, with a median survival rate of 7.2 months (Global burden of cancer 2013 JAMA Oncol 2015 (Global burden of cancer 2013 JAMA Oncol 2015). 1) 505-527). Despite the approval and widespread use of sorafenib (SOC), the prognosis for patients with advanced hepatocellular carcinoma (HCC) remains poor. In recent years, a highly tumorigenic subpopulation of cancer cells, named cancer stem cells (CSCs), has been said to be involved in post-treatment tumor recurrence. In fact, CSCs are resistant to chemotherapy and have the ability to regenerate all types of cells within the tumor. Therefore, innovative drugs that have an intrinsic mechanism of action and can combat CSC will improve the patient's cancer treatment. In this context, we decided to address the entire compartment and cell culture environment by developing an unbiased phenotypic cell screening assay.

Therefore, with the above considerations, there is a constant need for active compounds with improved effects or reduced side effects that can aid in the prevention and treatment of neoplasmic and non-neoplastic proliferative disorders such as cancer. I understand.

In particular, there is a need for such active compounds that can help address the issue of cancer resistance.

(Disclosure of Invention)
Unexpectedly, it was discovered that certain substituted 2-amino-4-2-grade amino-quinoline derivatives surprisingly exhibit potent antiproliferative and cytotoxic effects on certain cancer cell lines. Applicants have demonstrated in experiments that the compounds of the invention exhibit significant antiproliferative and cytotoxic effects on at least 7 human cancer cell lines. This antiproliferative activity suggests that the compounds of the present invention are useful in the treatment of a wide variety of disorders associated with abnormal cell proliferation. These disorders or diseases may be of neoplastic nature such as malignant neoplasms or non-neoplastic properties such as benign tumors and psoriasis. That is, the compounds of the present invention and compositions containing them can be used for the treatment and prevention of any disorder (malignant or non-malignant) of cell proliferation or cell differentiation. They can also be used to treat cancer, metastatic cancer, drug resistant cancer, or radiation resistant cancer. In addition, the compounds of the invention and compositions containing them can be used to sensitize subjects to other therapies such as radiation therapy, or to be used as maintenance therapies for cancer patients. You can also. In addition, this class of compounds also exhibits additional activity against human cancer stem cells (CSCs), which are widely recognized as responsible for the recurrence of cancer after anticancer treatment. The tumor sphere formation assay was used as a cancer stem cell functional function marker to explain its activity against CSC (Tovar, V. et al. Gut 2015 (0) 1-11, Hashimoto, N. . et al. BMC Cancer 2014 (14) 722). Another object of the present invention is to provide a method for inhibiting the proliferation or differentiation of cancer stem cells (CSCs), tumor-initiating cells, cancer-related mesenchymal-like cells, mesenchymal cancer cells, or mesenchymal cells. be.

［ここで、
・Ｌ^１は、単結合、又は置換もしくは非置換アルキレン、置換もしくは非置換アルケニレン、又は置換もしくは非置換アルキニレンであり；
・Ｌ^２は、単結合、カルボニル、置換もしくは非置換アルキレン、置換もしくは非置換アルケニレン、又は置換もしくは非置換アルキニレンであり；
・Ｒ^１は、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリール、置換もしくは非置換アリーレン、又は置換もしくは非置換ヘテロアリーレンであり；
・Ｒ^２は、ヒドロキシル、置換もしくは非置換アルコキシ、置換もしくは非置換アリールオキシ、置換もしくは非置換ヘテロアリールオキシ、置換もしくは非置換アルコキシカルボニルアミノ、置換もしくは非置換アリールオキシカルボニルアミノ、置換もしくは非置換ヘテロアリールオキシカルボニルアミノ、置換もしくは非置換アルキルアミノカルボニルアミノ、置換もしくは非置換アリールアミノカルボニルアミノ、置換もしくは非置換ヘテロアリールアミノカルボニルアミノ、又はＮＲ^５Ｒ^６（ここで、各Ｒ^５及びＲ^６は、独立してＨ、置換もしくは非置換アルキル、置換もしくは非置換シクロアルキル、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリール、又は置換もしくは非置換ヘテロシクロアルキルであるか、又はＲ^５及びＲ^６は、それらが結合している窒素原子と一緒になって、置換もしくは非置換複素環を形成する）であり；
・Ｑ_１、Ｑ_２、Ｑ_３、及びＱ_４は、それぞれ独立して、Ｈ、ヒドロキシル、ハロ、アミノ、ニトロ、チオール、カルボキシル、シアノ、アジド、置換もしくは非置換アルキル、置換もしくは非置換アルケニル、置換もしくは非置換アルキニル、置換もしくは非置換シクロアルキル、置換もしくは非置換シクロアルケニル、置換もしくは非置換アリールアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリール、置換もしくは非置換アルコキシ、置換もしくは非置換アリールオキシ、置換もしくは非置換ヘテロアリールオキシ、置換もしくは非置換スルファニル、置換もしくは非置換アルキルアミノ、置換もしくは非置換ジアルキルアミノ、置換もしくは非置換アリールアミノ、置換もしくは非置換ヘテロアリールアミノ、置換もしくは非置換アシル、置換もしくは非置換アシルアミノ、置換もしくは非置換アミノカルボニル、置換もしくは非置換アルコキシカルボニル、置換もしくは非置換アリールオキシカルボニル、置換もしくは非置換ヘテロアリールオキシカルボニル、置換スルホ、置換スルホニル、置換スルフィニル、置換もしくは非置換アミノスルホニル、置換もしくは非置換スルホニルアミノ、置換もしくは非置換アミノカルボニルアミノ、置換もしくは非置換アミノカルボニルオキシ、置換もしくは非置換アルコキシカルボニルアミノ、置換もしくは非置換アリールオキシカルボニルアミノ、又は置換もしくは非置換ヘテロアリールオキシカルボニルアミノであり；
・Ｒ^３ａは、Ｈ、ハロ、シアノ、置換もしくは非置換アルキル、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリール、置換もしくは非置換シクロアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アルコキシ、置換もしくは非置換アルコキシカルボニル、置換もしくは非置換アリールオキシカルボニル、置換もしくは非置換ヘテロアリールオキシカルボニル、又は置換もしくは非置換アミノカルボニルであり；
・各Ｒ^３ｂは、独立してＨ、ヒドロキシル、ハロ、アジド、アミノ、ニトロ、チオール、シアノ、カルボキシル、置換もしくは非置換アルキル、置換もしくは非置換アルケニル、置換もしくは非置換アルキニル、置換もしくは非置換アリールアルキル、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリール、置換もしくは非置換シクロアルキル、置換もしくは非置換シクロアルケニル、又は置換もしくは非置換ヘテロシクロアルキルであり；
・Ｒ^３ｃは、Ｈ、置換もしくは非置換アルキル、置換もしくは非置換アルケニル、置換もしくは非置換アルキニル、置換もしくは非置換シクロアルキル、置換もしくは非置換シクロアルケニル、又は置換もしくは非置換ヘテロシクロアルキルであるが、ただし、Ｒ^３ｃがＨである場合、Ｌ^２は単結合以外であるか、又はＲ^２はＮＲ^５Ｒ^６以外であるか、又はＲ^３ａはＨ以外であるか、又はＱ_１、Ｑ_２、Ｑ_３、及びＱ_４の少なくとも２つはＨ以外でかつ別個であり；
・Ｗは、場合により存在し、存在する場合は、Ｈ，ヒドロキシル、ハロ、アジド、アミノ、ニトロ、チオール、シアノ、カルボキシル、置換もしくは非置換アルキル、置換もしくは非置換アルケニル、置換もしくは非置換アルキニル、置換もしくは非置換アリールアルキル、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリール、置換もしくは非置換シクロアルキル、置換もしくは非置換シクロアルケニル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アルコキシ、置換もしくは非置換アリールオキシ、置換もしくは非置換ヘテロアリールオキシ、置換もしくは非置換スルファニル、置換もしくは非置換アルキルアミノ、置換もしくは非置換ジアルキルアミノ、置換もしくは非置換アリールアミノ、置換もしくは非置換ヘテロアリールアミノ、置換もしくは非置換アシル、置換もしくは非置換アシルアミノ、置換もしくは非置換アミノカルボニル、置換もしくは非置換アルコキシカルボニル、置換もしくは非置換アリールオキシカーボニル、置換もしくは非置換ヘテロアリールオキシカルボニル、置換スルホ、置換スルホニル、置換スルフィニル、置換もしくは非置換アミノスルホニル、置換もしくは非置換スルホニルアミノ、置換もしくは非置換アルキルスルホニル、置換もしくは非置換アリールスルホニル、置換もしくは非置換アミノカルボニルアミノ、置換もしくは非置換アミノカルボニルオキシ、置換もしくは非置換アルコキシカルボニルアミノ、置換もしくは非置換アリールオキシカルボニルアミノ、又は置換もしくは非置換ヘテロアリールオキシカルボニルアミノであり；
・ｍは、０、１、２、３、又は４であり；
ｍが０である場合、ｄは独立して０、１、又は２であり；ｍが１である場合、ｄは独立して０、１、２、又は３であり；ｍが２である場合、ｄは独立して０、１、２、３、又は４であり；ｍが３である場合、ｄは独立して０、１、２、３、４、又は５であり、又はｍが４である場合、ｄは独立して０、１、２、３、４、５、又は６である］、 Therefore, in one embodiment, the present invention is a group of substituted 2-amino-4-2-class amino-quinoline compounds represented by structural formula (I):

[here,
L ¹ is a single bond, or substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted alkynylene;
L ² is a single bond, carbonyl, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted alkynylene;
R ¹ is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene;
R ² is hydroxyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted alkoxycarbonylamino, substituted or unsubstituted aryloxycarbonylamino, substituted or unsubstituted hetero. Aryloxycarbonylamino, substituted or unsubstituted alkylaminocarbonylamino, substituted or unsubstituted arylaminocarbonylamino, substituted or unsubstituted heteroarylaminocarbonylamino, or NR ⁵ R ⁶ (where R ⁵ and R ⁶ are respectively. Independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl, or R ⁵ and R ⁶ are , Together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocycle);
_{· Q 1, Q 2, Q} 3, and _{Q 4} each, independently, H, hydroxyl, halo, amino, nitro, thiol, carboxyl, cyano, azido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, Substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or Unsubstituted alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted sulfanyl, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted arylamino, substituted or unsubstituted. Heteroarylamino, substituted or unsubstituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted sulfo, Substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted sulfonylamino, substituted or unsubstituted aminocarbonylamino, substituted or unsubstituted aminocarbonyloxy, substituted or unsubstituted alkoxycarbonylamino, substituted or unsubstituted aryloxy It is a carbonylamino, or a substituted or unsubstituted heteroaryloxycarbonylamino;
R ^3a is H, halo, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkoxy. , Substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, or substituted or unsubstituted aminocarbonyl;
Each R ^3b is independently H, hydroxyl, halo, azide, amino, nitro, thiol, cyano, carboxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl. Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocycloalkyl;
R ^3c is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocycloalkyl. However, if R ^3c is H, then L ² is something other than a single bond, or R ² is something other than ^{NR 5} R ^{6 , or R 3a} is something other than H, or Q ₁ , Q ₂ , _{Q 3,} and at least two _{Q 4} are a distinct and other than H;
W is present in some cases, and if present, H, hydroxyl, halo, azido, amino, nitro, thiol, cyano, carboxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, Substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkoxy, substituted or Unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted sulfanyl, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted arylamino, substituted or unsubstituted heteroarylamino, substituted or Unsubstituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted sulfo, substituted sulfonyl, substituted sulfinyl, Substituted or unsubstituted aminosulfonyl, substituted or unsubstituted sulfonylamino, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted aminocarbonylamino, substituted or unsubstituted aminocarbonyloxy, substituted or unsubstituted alkoxycarbonyl Amino, substituted or unsubstituted aryloxycarbonylamino, or substituted or unsubstituted heteroaryloxycarbonylamino;
M is 0, 1, 2, 3, or 4;
If m is 0, d is independently 0, 1, or 2; if m is 1, d is independently 0, 1, 2, or 3; if m is 2. , D independently are 0, 1, 2, 3, or 4; if m is 3, then d is independently 0, 1, 2, 3, 4, or 5, or m is 4 If d is independently 0, 1, 2, 3, 4, 5, or 6],

Alternatively, the present invention relates to a pharmaceutically acceptable salt, hydrate, solvate, or prodrug, or an isotope variant, tautomer, or stereoisomer thereof.

Other preferred embodiments of the invention are presented below, and any combination of any two or more of these embodiments is considered to be within the scope of the invention.

· Preferred embodiment, L ¹ is a single bond, or a substituted or unsubstituted alkylene, provides compounds of formula (I).
Another preferred embodiment ^{provides a compound of formula (I), wherein L 2} is a single bond, carbonyl, substituted or unsubstituted alkylene.
Yet another preferred embodiment of the invention is that R ² is hydroxyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, or NR ⁵ R ⁶ (where each). Whether R ⁵ and R ⁶ are independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl. Alternatively, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocycle), providing a compound of formula (I). In another preferred embodiment, the invention provides a compound of formula (I) where m is 0, 1, or 2.
In yet another preferred embodiment, the invention is that R ^3a is H, halo, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxycarbonyl, and each R ^3b is H independently. The compound of the formula (I) is provided.
• In yet another preferred embodiment, the invention ^{provides a compound of formula (I), wherein R 3c} is H, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl.
• In a specific embodiment, the invention is of _{formula (I), wherein Q 1} , Q ₂ , Q ₃ and Q ₄ are H, halo, cyano, or substituted or unsubstituted alkyl, respectively. Provide compounds.
Another specific embodiment of the invention provides a compound of formula (I) ^{, where L 2} is a single bond and R ² is NR ⁵ R ^6.
In another embodiment, the present invention comprises ^{formula (I) where L 1} is a substituted or unsubstituted alkylene, a substituted or unsubstituted alkenylene, or a substituted or unsubstituted alkynylene and R ¹ is a substituted or unsubstituted allylene. Compounds are provided.
In a further embodiment, the invention is that L ¹ is a substituted or unsubstituted alkylene, a substituted or unsubstituted alkenylene, or a substituted or unsubstituted alkynylene, R ¹ is a substituted or unsubstituted arylene, and W is a halo. A compound of formula (I) is provided.
In a further preferred embodiment of the invention, the substituted or unsubstituted arylene is substituted or unsubstituted phenylene-1,4-diyl, substituted or unsubstituted phenylene-1,3-diyl, or substituted or unsubstituted naphthalene-1. , 4-Zyl, the compound of formula (I) is provided.
A further preferred embodiment of the invention is that each R ^3b is H and m is 0, 1, or 2; if m is 0, d is 2; if m is 1. d provides a compound of formula (I), where d is 3 independently; or where m is 2, d is 4.
In a further preferred embodiment of the invention, L ¹ is −CH ₂ −, R ¹ is a substituted or unsubstituted arylene, where the substituted or unsubstituted arylene group is a substituted or unsubstituted phenylene-1. , 4-Diyl, substituted or unsubstituted phenylene-1,3-diyl, or substituted or unsubstituted naphthalene-1,4-diyl, provided is a compound of formula (I).
In a preferred embodiment, L ¹ is −CH ₂ −; R ¹ is substituted or unsubstituted phenylene-1,4-diyl, or substituted or unsubstituted phenylene-1,3-diyl. , ^{R 3a,} provides H, halo, CN, substituted or unsubstituted _C 1 -C ₆ alkyl, or substituted or unsubstituted alkoxycarbonyl, a compound of formula (I).
• In another preferred embodiment, the invention provides a compound of formula (I) ^{, where L 1} is a single bond and R ^{1 is a substituted or unsubstituted arylene.}
-In another preferred embodiment, the invention provides a compound of formula (I), wherein W is a substituted or unsubstituted heteroarylamino.
In a preferred embodiment, L ¹ is a single bond; R ¹ is a substituted or unsubstituted arylene; W is a substituted or unsubstituted heteroarylamino ^{; each R 3b} is H; m is 0, 1 or 2; if m is 0, d is 2; if m is 1, d is 3 independently; or if m is 2, d is 4. The compound of formula (I) is disclosed.
• In another preferred embodiment, R ¹ is substituted or unsubstituted phenylene-1,4-diyl, substituted or unsubstituted phenylene-1,3-diyl, or substituted or unsubstituted naphthalene-1,4; R. ^{Disclosed is a compound of formula (I), wherein 3a} is a halo, a cyano, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkoxycarbonyl.
• In yet another preferred embodiment, ^{the compound of formula (I) is disclosed, wherein R 1} is substituted or unsubstituted phenylene-1,4-diyl, or substituted or unsubstituted phenylene-1,3-diyl. NS.
• In a preferred embodiment, the invention ^{provides a compound of formula (I), where L 1} is a single bond; R ¹ is a substituted or unsubstituted heteroaryllen; W is a substituted or unsubstituted heteroarylamino. do.
In another preferred embodiment, the invention is that L ¹ is a single bond; R ¹ is a substituted or unsubstituted heteroarylene; W is a substituted or unsubstituted heteroarylamino; each R ^3b is H. Yes; m is 0, 1, or 2; if m is 0, d is 2; if m is 1, d is 3 independently; or if m is 2. d provides a compound of formula (I), which is 4.
-In a more preferred embodiment, the invention is that R ¹ is substituted or unsubstituted pyridinediyl, substituted or unsubstituted pyrimidindiyl, substituted or unsubstituted pyrazinediyl, substituted or unsubstituted 1H-pyrazoldiyl, oxazolediyl, or substituted or non-substituted. a substituted isoxazolediyl; R ^3a, provides halo, cyano, or substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted alkoxycarbonyl, a compound of formula (I).
-In a further preferred embodiment, the invention is that R ¹ is substituted or unsubstituted pyridine-2,4-diyl, substituted or unsubstituted pyridine-2,5-diyl, or substituted or unsubstituted pyridine-2,6-diyl. The compound of the formula (I) is provided. In a further preferred embodiment, W is a pyrimidine-2-yl-amino, pyrimidine-4-yl-amino, pyrimidine-5-yl-amino, 1H-pyrazole-5-yl-amino, 1H-pyrazole. -4-yl-amino, flo [2,3-d] pyrimidine-2-yl-amino, pyridin-2-yl-amino, pyridin-3-yl-amino, or pyridine-4-yl-amino, The compound of the formula (I) is provided.

• In a further embodiment, a compound selected from the group consisting of:
2- (4-Chlorobenzylamino) -4- [3- (pyrrolidin-1-yl) azetidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -4- [3- (morpholine-4-yl) azetidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -4- [4- (methylcarbamoyl) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -4- [4- (tert-butylaminocarbonyl) -piperidine-1-yl] -quinoline,
2- (4-Chlorobenzylamino) -4- [4- (pyrrolidin-1-carbonyl) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -4- [4- (4-methylpiperazine-1-carbonyl) -piperidine-1-yl] -quinoline,
(2S) 2- (4-chlorobenzylamino) -4- [2- (hydroxymethyl) pyrrolidine-1-yl] quinoline,
(2S) 2- (4-chlorobenzylamino) -4- [2- (methoxymethyl) pyrrolidine-1-yl] quinoline,
(2R) -2- (4-chlorobenzylamino) -4- [2- (hydroxymethyl) -pyrrolidin-1-yl] -quinoline,
2- (4-Chlorobenzylamino) -4- (4-hydroxypiperidine-1-yl) quinoline,
2- (4-Chlorobenzylamino) -4- [4- (iso-propoxy) -piperidine-1-yl] -quinoline,
2- (4-Chlorobenzylamino) -4- (4-phenoxypiperidine-1-yl) -quinoline,
2- (4-Chlorobenzylamino) -4- [4- (m-tolyloxy) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -4- [4- (pyridin-4-yloxy) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -4- [4- (pyrazine-2-yloxy) piperidine-1-yl] quinoline,
(3R) 2- (4-chlorobenzylamino) -4- (3-hydroxypyrrolidin-1-yl) quinoline,
(3R) 2- (4-chlorobenzylamino) -4- [3- (phenoxy) pyrrolidine-1-yl] quinoline,
(3R) 2- (4-chlorobenzylamino) -4- [3- (pyridin-2-yloxy) pyrrolidine-1-yl] quinoline,
(3S) 2- (4-chlorobenzylamino) -4- (3-hydroxypyrrolidin-1-yl) -quinoline,
(3S) 2- (4-chlorobenzylamino) -4- [3- (pyridin-2-yloxy) pyrrolidine-1-yl] quinoline,
2- (N-4-chlorobenzyl-N-methylamino) -4- [4- (tert-butylamino) -piperidine-1-yl] -quinoline,
2- (N-4-chlorobenzyl-N-ethylamino) -4- [4- (tert-butylamino) -piperidine-1-yl] -quinoline,
2- (N-4-chlorobenzyl-N-isopropylamino) -4- [4- (tert-butylamino) -piperidine-1-yl] -quinoline,
2- (N-4-chlorobenzyl-N-isobutylamino) -4- [4- (tert-butylamino) -piperidine-1-yl] -quinoline,
2- (4-Chlorobenzylamino) -3-fluoro-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-methyl-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
Methyl 4- (4- (tert-butylamino) piperidine-1-yl) -2- (4-chlorobenzylamino) quinoline-3-carboxylate,
2- (4-Chlorobenzylamino) -4- [4- (tert-butylamino) piperidine-1-yl] -7-methyl-8-fluoroquinoline,
2- (4-Chlorobenzylamino) -4- [4- (tert-butylamino) piperidine-1-yl] -6-methyl-8-fluoroquinoline,
2- (4-Chlorobenzylamino) -4- [4- (tert-butylamino) piperidine-1-yl] -7-fluoro-8-methylquinoline,
2- (4-Chlorobenzylamino) -4- [4- (tert-butylamino) piperidine-1-yl] -6-fluoro-8-methylquinoline,
2- [4- (4-Methylpyrimidine-2-ylamino) phenylamino] -3-methyl-4- (4-tert-butylaminopiperidine-1-yl) quinoline,
2- [3- (4-Trifluoromethylpyrimidine-2-ylamino) phenylamino] -3-methyl-4- (4-tert-butylaminopiperidine-1-yl) quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- [4- (4- (Pyridine-3-yl) pyrimidin-2-ylamino) -3-methylbenzylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline,
2- (3-Methyl-4- (4-methylpyrimidine-2-ylamino) phenylamino) -3-cyano-4- (4- (tert-butylamino) piperidine-1-yl) -quinoline,
2- [4- (4,6-dimethyl-2-pyrimidineamino) -3-methyl-phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline,
2- [4- (4-Methyl-6-Methoxypyrimidine-2-ylamino) -3-methylphenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline,
2- [3-Methyl-4- (4,6-dimethylflo [2,3-d] pyrimidin-2-ylamino) Phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) ) Quinoline,
2- {3-Methyl-4- [2- (pyridin-3-yl) pyrimidin-4-ylamino] phenylamino} -3-cyano-4- (4-tert-butylaminopiperidin-1-yl) quinoline,
2- {3-Methyl-4- [2- (pyridin-3-yl) -5-cyanopyrimidine-4-ylamino] phenylamino} -3-cyano-4- (4-tert-butylaminopiperidine-1-) Il) quinoline,
2- [4- (4-Methylpyrimidine-2-ylamino) phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline,
2- [3-Methyl-4- (4-trifluoromethylpyrimidine-2-ylamino) phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline,
2- [3- (4-Trifluoromethyl-2-pyrimidineamino) -4-methyl-phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline,
2- [3- (4-Trifluoromethylpyrimidine-2-ylamino) phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline,
2- [4- (4- (Pyridine-3-yl) pyrimidin-2-ylamino) -3-methylphenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline,
2- [3- (4-Trifluoromethylpyrimidine-2-ylamino) phenylamino] -3-fluoro-4- (4-tert-butylaminopiperidine-1-yl) quinoline,
2- (4-Fluorobenzylamino) -3-fluoro-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (4-Fluorobenzylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] -8-methylquinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] -7-methylquinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] -6-methylquinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- (3-aminopiperidin-1-yl) quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (methylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (isopropylamino) piperidine-1-yl] quinoline,
{[(Tetrahydro-2H-pyra-4-yl) methyl] amino} -3-fluoro-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (cyclopentylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (4-methylpiperazine-1-yl) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4-{3-[(1-methylpiperidine-4-yl) amino] piperidine-1-yl} quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (pyrrolidin-1-yl) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (morpholino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (4-methylpiperazine-1-yl) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (dimethylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (diethylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- (4-aminopiperidine-1-yl) quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (methylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (isopropylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4-{4-[(tert-butyloxycarbonyl) amino] piperidine-1-yl} quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (cyclopentylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4-{4-[(tetrahydro-2H-pyran-4-yl) amino] piperidine-1-yl} quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4-{4-[(1-methylpiperidine-4-yl) amino] piperidine-1-yl} quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (pyrrolidin-1-yl) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (morpholino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (4-methylpiperazine-1-yl) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (dimethylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (diethylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3-aminopyrrolidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (methylamino) pyrrolidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (cyclopentylamino) pyrrolidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4-{3-[(tetrahydro-2H-pyran-4-yl) amino] pyrrolidine-1-yl} quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (pyrrolidin-1-yl) pyrrolidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- (3-morpholinopyrrolidine-1-yl) quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (4-methylpiperazin-1-yl) pyrrolidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (dimethylamino) pyrrolidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (diethylamino) pyrrolidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- (3-phenoxypiperidine-1-yl) quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (4-methoxyphenoxy) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (4-methylphenoxy) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (4-fluorophenoxy) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (3-fluorophenoxy) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4-{3-[(3-methylpyrazine-2-yl) oxy] piperidine-1-yl} quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- (4-phenoxypiperidine-1-yl) quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (4-methoxyphenoxy) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (p-tolyloxy) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (4-chlorophenoxy) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (4-fluorophenoxy) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (3-fluorophenoxy) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4-{4-[(pyridin-4-yl) oxy] piperidine-1-yl} quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4-{4-[(5-methylisoxazole-3-yl) oxy] piperidine-1-yl} quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4-{4-[(3-methylpyrazine-2-yl) oxy] piperidine-1-yl} quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- (3-phenoxypyrrolidine-1-yl) quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (4-methylphenoxy) pyrrolidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (4-methoxyphenoxy) pyrrolidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (4-chlorophenoxy) pyrrolidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (4-fluorophenoxy) pyrrolidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (3-fluorophenoxy) pyrrolidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4-{3-[(3-methylpyrazine-2-yl) oxy] pyrrolidine-1-yl} quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4-{3-[(pyridin-4-yl) oxy] pyrrolidine-1-yl} quinoline,
2- (Phenylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (4-Methylphenylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (3-Methyl-4-fluorophenylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (4-Methoxyphenylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (2-Trifluoromethylphenylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (3-Trifluoromethylphenylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (4-Chlorophenylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (4-Fluorophenylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (3-Fluorophenylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (3,4-difluorophenylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- [4- (trifluoromethyloxy) phenylamino] -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2-[(1-Methyl-1H-pyrazole-4-yl) amino] -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2-[(1-Methyl-1H-1,2,4-triazole-5-yl) amino] -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2-[(1,3-dimethyl-1H-1,2,4-triazole-5-yl) amino] -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- {4- [(4,6-dimethylpyrimidine-2-yl) amino] phenylamino} -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (Pyridine-2-ylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (Pyrimidine-2-ylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (Pyrimidine-4-ylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (Pyrazine-2-ylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (Benzylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (4-Methylbenzylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (4-Methoxybenzylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- [4- (Trifluoromethyl) benzylamino] -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- [2- (Trifluoromethyl) benzylamino] -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2-[(Benzo [d] [1,3] dioxol-5-ylmethyl) amino] -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2-[(Fran-2-ylmethyl) amino] -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2-[(Pyridine-3-ylmethyl) amino] -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2-[(Pyridine-4-ylmethyl) amino] -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2-[(Pyridine-2-ylmethyl) amino] -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,

Or pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof, or isotopic variants, tautomers, or stereoisomers thereof are disclosed.

［ここで
−Ｌ^２は、単結合、カルボニル、置換もしくは非置換アルキレン、置換もしくは非置換アルケニレン、又は置換もしくは非置換アルキニレンであり；
−Ｒ^２は、ヒドロキシル、置換もしくは非置換アルコキシ、置換もしくは非置換アリールオキシ、置換もしくは非置換ヘテロアリールオキシ、置換もしくは非置換アルコキシカルボニルアミノ、置換もしくは非置換アリールオキシカルボニルアミノ、置換もしくは非置換ヘテロアリールオキシカルボニルアミノ、置換もしくは非置換アルキルアミノカルボニルアミノ、置換もしくは非置換アリールアミノカルボニルアミノ、置換もしくは非置換ヘテロアリールアミノカルボニルアミノ、又はＮＲ^５Ｒ^６（ここで、各Ｒ^５及びＲ^６は、独立してＨ、置換もしくは非置換アルキル、置換もしくは非置換シクロアルキル、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリール、又は置換もしくは非置換ヘテロシクロアルキルであるか、又はＲ^５及びＲ^６は、それらが結合している窒素原子と一緒になって、置換もしくは非置換複素環を形成する）であり；
−Ｒ^３ａは、Ｈ、ハロ、シアノ、置換もしくは非置換アルキル、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリール、置換もしくは非置換シクロアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アルコキシ、置換もしくは非置換アルコキシカルボニル、置換もしくは非置換アリールオキシカルボニル、置換もしくは非置換ヘテロアリールオキシカルボニル、又は置換もしくは非置換アミノカルボニルであり；
−各Ｒ^３ｂは、独立してＨ、ヒドロキシル、ハロ、アジド、アミノ、ニトロ、チオール、シアノ、カルボキシル、置換もしくは非置換アルキル、置換もしくは非置換アルケニル、置換もしくは非置換アルキニル、置換もしくは非置換アリールアルキル、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリール、置換もしくは非置換シクロアルキル、置換もしくは非置換シクロアルケニル、又は置換もしくは非置換ヘテロシクロアルキルであり；
−Ｒ^３ｃは、Ｈ、置換もしくは非置換アルキル、置換もしくは非置換アルケニル、置換もしくは非置換アルキニル、置換もしくは非置換シクロアルキル、置換もしくは非置換シクロアルケニル、又は置換もしくは非置換ヘテロシクロアルキルであるが、ただし、Ｒ^３ｃがＨである場合、Ｌ^２は単結合以外であるか、又はＲ^２はＮＲ^５Ｒ^６以外であるか、又はＲ^３ａはＨ以外であり；
−ｍは、０、１、２、３、又は４であり；
ｍが０である場合、ｄは独立して０、１、又は２であり；ｍが１である場合、ｄは独立して０、１、２、又は３であり；ｍが２である場合、ｄは独立して０、１、２、３、又は４であり；ｍが３である場合、ｄは独立して０、１、２、３、４、又は５であり、又はｍが４である場合、ｄは独立して０、１、２、３、４、５、又は６である］、 In a preferred embodiment, the compound of formula (II):

[Here-L ² is a single bond, carbonyl, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted alkynylene;
-R ² is hydroxyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted alkoxycarbonylamino, substituted or unsubstituted aryloxycarbonylamino, substituted or unsubstituted hetero. Aryloxycarbonylamino, substituted or unsubstituted alkylaminocarbonylamino, substituted or unsubstituted arylaminocarbonylamino, substituted or unsubstituted heteroarylaminocarbonylamino, or NR ⁵ R ⁶ (where R ⁵ and R ⁶ are respectively. Independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl, or R ⁵ and R ⁶ are , Together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocycle);
-R ^3a is H, halo, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkoxy. , Substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, or substituted or unsubstituted aminocarbonyl;
^-Each R 3b is independently H, hydroxyl, halo, azide, amino, nitro, thiol, cyano, carboxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl. Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocycloalkyl;
-R ^3c is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocycloalkyl. However, if R ^3c is H, then L ² is something other than a single bond, or R ² is something other than ^{NR 5} R ^{6 , or R 3a} is something other than H;
−M is 0, 1, 2, 3, or 4;
If m is 0, d is independently 0, 1, or 2; if m is 1, d is independently 0, 1, 2, or 3; if m is 2. , D independently are 0, 1, 2, 3, or 4; if m is 3, then d is independently 0, 1, 2, 3, 4, or 5, or m is 4 If d is independently 0, 1, 2, 3, 4, 5, or 6],

Alternatively, a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, or an isotope variant, tautomer, or stereoisomer thereof is provided.

In a preferred embodiment, ^{compounds of formula (II) are provided in which R 3c} is H, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl.
• In another preferred embodiment, compounds of formula (II) are provided ^{, wherein each R 3b is H independently.}
-In a further preferred embodiment, ^{compounds of formula (II) are provided in which R 3a} is H, halo, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxycarbonyl. Preferably, the halo atom is fluorine.
-In yet still more preferred embodiments, ^{compounds of formula (II) are provided in which L 2} is a single bond, carbonyl, substituted or unsubstituted alkylene.
• In still more preferred embodiments, compounds of formula (II) are provided, wherein m is 0, 1, or 2.

［ここで：
−Ｑ_１、Ｑ_２、Ｑ_３、及びＱ_４は、それぞれ独立して、Ｈ、ヒドロキシル、ハロ、アミノ、ニトロ、チオール、カルボキシル、シアノ、アジド、置換もしくは非置換アルキル、置換もしくは非置換アルケニル、置換もしくは非置換アルキニル、置換もしくは非置換シクロアルキル、置換もしくは非置換シクロアルケニル、置換もしくは非置換アリールアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリール、置換もしくは非置換アルコキシ、置換もしくは非置換アリールオキシ、置換もしくは非置換ヘテロアリールオキシ、置換もしくは非置換スルファニル、置換もしくは非置換アルキルアミノ、置換もしくは非置換ジアルキルアミノ、置換もしくは非置換アリールアミノ、置換もしくは非置換ヘテロアリールアミノ、置換もしくは非置換アシル、置換もしくは非置換アシルアミノ、置換もしくは非置換アミノカルボニル、置換もしくは非置換アルコキシカルボニル、置換もしくは非置換アリールオキシカルボニル、置換もしくは非置換ヘテロアリールオキシカルボニル、置換スルホ、置換スルホニル、置換スルフィニル、置換もしくは非置換アミノスルホニル、置換もしくは非置換スルホニルアミノ、置換もしくは非置換アミノカルボニルアミノ、置換もしくは非置換アミノカルボニルオキシ、置換もしくは非置換アルコキシカルボニルアミノ、置換もしくは非置換アリールオキシカルボニルアミノ、又は置換もしくは非置換ヘテロアリールオキシカルボニルアミノであり；Ｑ_１、Ｑ_２、Ｑ_３、及びＱ_４の少なくとも２個はＨ以外であり、かつ別個である］。 The present invention also provides, in a preferred embodiment, a compound of formula (III) having the following structure:

[here:
-Q ₁ , Q ₂ , Q ₃ and Q ₄ are independently H, hydroxyl, halo, amino, nitro, thiol, carboxyl, cyano, azide, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, respectively. Substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or Unsubstituted alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted sulfanyl, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted arylamino, substituted or unsubstituted. Heteroarylamino, substituted or unsubstituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted sulfo, Substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted sulfonylamino, substituted or unsubstituted aminocarbonylamino, substituted or unsubstituted aminocarbonyloxy, substituted or unsubstituted alkoxycarbonylamino, substituted or unsubstituted aryloxy carbonyl, amino, or substituted or unsubstituted heteroaryl _{aryloxycarbonylamino;} Q _1, at least two Q 2, _{Q 3,} and _{Q 4} is other than H, and a separate.

· Present invention in a further _{embodiment, Q 1, Q 2, Q} 3, and _{Q 4} are each independently H, cyano, methyl, or halo provides a compound of formula (III).

［ここで
−Ｒ^３ａは、ハロ、シアノ、置換もしくは非置換アルキル、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリール、置換もしくは非置換シクロアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アルコキシ、置換もしくは非置換アルコキシカルボニル、置換もしくは非置換アリールオキシカルボニル、置換もしくは非置換ヘテロアリールオキシカルボニル、又は置換もしくは非置換アミノカルボニルであり；
−Ｌ^１は、単結合、又は置換もしくは非置換アルキレン、置換もしくは非置換アルケニレン、又は置換もしくは非置換アルキニレンであり；
−Ｒ^１は、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリール、置換もしくは非置換アリーレン、又は置換もしくは非置換ヘテロアリーレンであり；
−Ｗは、場合により存在し、存在する場合は、Ｈ，ヒドロキシル、ハロ、アジド、アミノ、ニトロ、チオール、シアノ、カルボキシル、置換もしくは非置換アルキル、置換もしくは非置換アルケニル、置換もしくは非置換アルキニル、置換もしくは非置換アリールアルキル、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリール、置換もしくは非置換シクロアルキル、置換もしくは非置換シクロアルケニル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アルコキシ、置換もしくは非置換アリールオキシ、置換もしくは非置換ヘテロアリールオキシ、置換もしくは非置換スルファニル、置換もしくは非置換アルキルアミノ、置換もしくは非置換ジアルキルアミノ、置換もしくは非置換アリールアミノ、置換もしくは非置換ヘテロアリールアミノ、置換もしくは非置換アシル、置換もしくは非置換アシルアミノ、置換もしくは非置換アミノカルボニル、置換もしくは非置換アルコキシカルボニル、置換もしくは非置換アリールオキシカーボニル、置換もしくは非置換ヘテロアリールオキシカルボニル、置換スルホ、置換スルホニル、置換スルフィニル、置換もしくは非置換アミノスルホニル、置換もしくは非置換スルホニルアミノ、置換もしくは非置換アルキルスルホニル、置換もしくは非置換アリールスルホニル、置換もしくは非置換アミノカルボニルアミノ、置換もしくは非置換アミノカルボニルオキシ、置換もしくは非置換アルコキシカルボニルアミノ、置換もしくは非置換アリールオキシカルボニルアミノ、又は置換もしくは非置換ヘテロアリールオキシカルボニルアミノである］。 The present invention also provides, in a preferred embodiment, a compound of formula (IV) having the following structure:

[Here, -R ^3a is halo, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted. Alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, or substituted or unsubstituted aminocarbonyl;
-L ¹ is a single bond, or substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted alkynylene;
-R ¹ is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene;
-W may be present, and if present, H, hydroxyl, halo, azido, amino, nitro, thiol, cyano, carboxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, Substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkoxy, substituted or Unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted sulfanyl, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted arylamino, substituted or unsubstituted heteroarylamino, substituted or Unsubstituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted sulfo, substituted sulfonyl, substituted sulfinyl, Substituted or unsubstituted aminosulfonyl, substituted or unsubstituted sulfonylamino, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted aminocarbonylamino, substituted or unsubstituted aminocarbonyloxy, substituted or unsubstituted alkoxycarbonyl Amino, substituted or unsubstituted aryloxycarbonylamino, or substituted or unsubstituted heteroaryloxycarbonylamino].

-In a more preferred embodiment, the invention ^{provides a compound of formula (IV), wherein R 3a} is a halo, cyano, or substituted or unsubstituted alkoxycarbonyl.
• In another preferred embodiment, the invention ^{provides a compound of formula (IV), wherein L 1} is a single bond, or substituted or unsubstituted alkylene.
• In yet another preferred embodiment, the invention ^{provides a compound of formula (IV), wherein R 1} is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl.
• In yet another preferred embodiment, the invention provides a compound of formula (IV), wherein W is a substituted or unsubstituted arylamino, or a substituted or unsubstituted heteroarylamino.

In another aspect, the invention is also a compound of the invention, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, or an isotope variant thereof, used pharmaceutically as they are. Provide a variant or a stereoisomer.

In a further aspect, the invention also comprises the compounds of the invention, or pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof, or isotopic variants, tautomers, or stereoisomers thereof. Provided is a pharmaceutical composition comprising a therapeutically effective amount of the above and a pharmaceutically acceptable excipient.

In yet another aspect, the invention also provides a method of treating a proliferative disorder, comprising administering the pharmaceutical composition of the invention to a patient in need.

In another aspect of the invention, a compound of the invention, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug, or isotope thereof for use in the treatment of proliferative disorders. Variants, tautomers, or stereoisomers are provided. Specifically, the proliferative disease is selected from neoplastic and non-neoplastic diseases. Specifically, the neoplastic disease is cancer. More specifically, the cancers are malignant tumors, malignant lymphomas, malignant melanomas, malignant stellate cell tumors, benign tumors, solid tumors, sarcomas, cancers, cartinoids, Ewing sarcomas, capsicum sarcomas, brain tumors, brain and / or nervous system. And / or medullary tumor, glioma, glioma, blastoma, gastric cancer, pancreatic cancer, kidney cancer, renal cell cancer, prostate cancer, prostate cancer, connective tissue tumor, soft tissue sarcoma, fiber Sarcoma, pancreatic tumor, liver cancer, head eye, cervical cancer, laryngeal cancer, nasopharyngeal cancer, esophageal cancer, colon cancer, thyroid cancer, osteosarcoma, retinal blastoma, thoracic adenomas, testis cancer, lung cancer, lung adenocarcinoma , Small cell lung cancer, bronchial cancer, breast cancer, breast cancer (mamma carcinoma), intestinal cancer, colon-rectal tumor, colon cancer, prostate cancer, rectal cancer, gynecological tumor, ovarian tumor, uterine cancer, cervical cancer (Cervical cancer), cervical cancer (cervix carcinoma), uterine body cancer, corpus cancer, endometrial cancer, bladder cancer, urogenital tract cancer, bladder cancer, skin cancer, epithelial tumor, squamous cell carcinoma, basal cell cancer, Basal cell tumor, myeloma, melanoma, intraocular melanoma, leukemia, monocytic leukemia, chronic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, acute leukemia, acute myeloid leukemia, acute premyelodystical leukemia (APL), acute Lymphocytic leukemia, acute T lymphoblastic leukemia, adult T-cell leukemia, basal leukemia, eosinophilic leukemia, granulocytic leukemia, hairy cell leukemia, leukopenia leukemia, lymphocytic leukemia, lymphoblastic leukemia Selected from the group consisting of globular leukemia, lymphocytic leukemia, macronuclear leukemia, small bone marrow blast leukemia, monocytic leukemia, neutrophil leukemia, stem cell leukemia, germ cell cancer, and metastatic proliferation. .. Specifically, the cancer is a liver cancer selected from the group consisting of hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma.

In a further aspect, the invention is also used to inhibit the growth or differentiation of cancer stem cells (CSCs), tumor-initiating cells, cancer-related mesenchymal-like cells, mesenchymal cancer cells, or mesenchymal cells. Provided are a compound of the present invention, or a pharmaceutically acceptable salt, hydrate, solvent, or prodrug thereof, or an isotope variant, a metamutant, or a steric isomer thereof.

In a preferred embodiment, the pharmaceutical composition of the invention further comprises at least one additional therapeutically active substance. Specifically, the additional therapeutically active substance is for the treatment of cancer.

In yet another embodiment, the invention is also a compound of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical for the treatment of proliferative disorders selected from neoplastic and non-neoplastic disorders. Provided are the use of hydrates, solvates, or prodrugs, or isotopic variants, tautomers, or stereoisomers thereof.

Prodrugs, stereoisomers, mixtures of stereoisomers, racemates, mutants, salts, hydrates, solvates of compounds having the structure of formula I (or II, III, III'or IV). , Salt hydrates, acid acid hydrates, and homomorphic crystal morphologies are also considered to be within the scope of the present invention.

The present invention is based on the recognition that compounds of formula (I) may be useful in the treatment of cell proliferation disorders, especially in mammals. The invention also provides methods of preparing the compounds of the invention, intermediates for their preparation, pharmaceutical compositions containing the compounds of the invention, and their use as pharmaceuticals for the treatment of cell proliferative disorders. do.

The section headings used herein are for structural purposes only and should not be construed as limiting the subject matter described. All documents or parts of the documents cited in this application, including, but not limited to, patents, patent applications, articles, books, manuals, and articles, are in their entirety for any purpose. Is explicitly taken in as a reference.

As used herein, the term "compound of the invention" and equivalent expressions are meant to include the compounds of the above general formula (I), where the expression is acceptable in the context. Includes pharmaceutically acceptable salts, hydrates, solvates, prodrugs, isotope variants, tautomers, steric isomers, and polymorphs thereof. Similarly, where the context allows, references to intermediates include their salts, solvates, and isotopic variants, whether or not they are claimed in their own right. means. For clarity, certain examples allowed in the context are sometimes given in the text, but these examples are purely exemplary and are not intended to exclude other examples as the context allows.

The phrase "as defined above" refers to the broadest definition of each group, as described in the outline of the invention or the broadest claims. In all other embodiments provided below, the non-explicitly defined substituents that may be present in each embodiment retain the broadest definition provided in the context of the invention.

Unless otherwise stated herein, the use of the singular includes the plural. It should be noted that as used herein and in the accompanying claims, the singular forms "a", "an", and "the" include multiple referents unless explicitly stated otherwise in the context. sea bream. As used herein, the use of "or" means "and / or" unless otherwise stated. Moreover, the use of other forms such as the terms "contains" and "contains" is not limiting.

Definitions of standard chemical terms are found in references including Carey and Sundberg “ADVANCED ORGANIC CHEMISTRY 5TH ED.” Vols. A (2008) and B (2010), Plenum Press, New York. Unless otherwise specified, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology within the skill of one of ordinary skill in the art are used. Unless otherwise specified, the nomenclature, and experimental procedures and techniques used in connection with analytical chemistry, synthetic organic chemistry, medicinal chemistry, and medicinal chemistry described herein are known in the art. .. Standard techniques can be used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation, delivery, and treatment of patients. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (eg, electroporation, lipofection). Reaction and purification techniques can be performed, for example, using kits specified by the manufacturer, or as commonly practiced in the art, or as described herein. The techniques and procedures described above are general as described in conventional methods known in the art and in various general and more specific references cited and discussed throughout this specification. Can be done.
It should be understood that the methods and compositions described herein are not limited to the particular methodologies, protocols, cell lines, constructs, and reagents described herein and are therefore variable. The terms used herein are for illustration purposes only and are not intended to limit the scope of the methods and compositions described herein, and are the scope of the appended claims. It should also be understood that it is limited only by.
All publications and patents referred to herein are incorporated herein by reference in their entirety, for example, for the purpose of describing and disclosing the constructs and methodologies described in that publication. Can be used in connection with the methods, compositions, and compounds described herein. The publications discussed herein are provided solely for their disclosure prior to the filing date of this application. It should not be understood that the inventor described herein acknowledges that he is not entitled to precede such disclosure by prior invention or for any other reason.

The definition term "independently" for substituents is used herein to mean that a variable applies to any one example, with or without the presence or absence of variables having the same or different definitions within the same compound. Used to indicate. That is, for example, ^{in a compound in which the substituent Y *} appears twice and is defined as "independently the group G1 or the group G2", whether both Y ^* are G1 or both Y ^* are G2. Well, or one Y ^* may be G1 and the other method may be G2.

The "alkyl" group refers to an aliphatic hydrocarbon group. The alkyl moiety may be a "saturated alkyl" group, which means that it is completely free of alkene or alkyne moieties. The alkyl moiety may also be an "unsaturated alkyl" moiety, which means that it comprises at least one alkene or alkyne moiety. The "alkene" moiety refers to a group having at least one carbon-carbon double bond and the "alkyne" moiety refers to a group having at least one carbon-carbon triple bond. The alkyl moiety may be saturated or unsaturated, branched chain, straight chain, or cyclic (in this case also known as a "cycloalkyl" group). Depending on the structure, the alkyl group can be a monoradical or a diradical (also known as an "alkylene" group in this case). The alkyl group may also be a "lower alkyl" having 1 to 6 carbon atoms.

As used herein, C _{1 to} C _x include C _{1 to} C ₂ , C _{1 to} C ₃ , ... C _{1 to} C _x . .. As a mere example, "C _{1 to} C ₄ " contains 1 to 4 carbon atoms, that is, 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. group containing, as well as a group from _C 1 -C ₂ and in the appended _C 1 -C _3. Therefore, as a mere example, "C _{1 to} C ₄ alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl group, that is, this alkyl group is methyl, ethyl, propyl, isopropyl, n-. It is selected from butyl, isobutyl, sec-butyl, and t-butyl. Whenever it appears herein, a numerical range such as "1-10" refers to each integer within a given range. For example, "1 to 10 carbon atoms" means 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, and 7 carbon atoms. It means that it has 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.

The "alkyl" moiety may have 1 to 10 carbon atoms (whenever appearing herein, a numerical range such as "1-10" refers to each integer within a given range. For example, in "1 to 10 carbon atoms", the alkyl group can have up to 10 carbon atoms such as 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. The definition also includes the presence of the term "alkyl" for which no numerical range is specified). Alkyl group of the compounds described herein can be represented by "C ₁ -C ₄ alkyl" or similar names. "C ₁ -C ₄ alkyl" as a mere example, indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain, methyl, ethyl, propyl, isopropyl, n- butyl, iso It is selected from -butyl, sec-butyl, and t-butyl. That is, C _{1 to} C ₄ alkyl includes C _{1 to} C ₂ alkyl and C _{1 to} C ₃ alkyl. The alkyl group may or may not be substituted. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, etc. Includes cyclohexyl and the like.

The term "alkylene" refers to an alkyl group in which the alkyl is a diradical as described above. Typically, the alkylene group has two binding points to the rest of the molecule (eg, −L ¹ − and / or ^{− L 2− in the} molecule represented by formula I of the invention). The two bonding points of an alkylene group can be located on one carbon atom or on two different carbon atoms.
The alkylene group may be branched or straight. The alkylene group may be unsaturated (in this case, it is also known as an "alkenylene" group or an "alkynylene" group). The alkylene group may be cyclic (in this case, it is also known as a "cycloalkylene" group). The alkylene group may or may not be substituted. The alkylene group can have 1 to 10 carbon atoms. Preferred alkylene groups have 1 to 8 carbon atoms. The most preferred alkylene group is one having 1 to 6 carbon atoms.
Typical alkylene group branched or straight chain, but are not limited to, methylene _(-CH 2 -), ethylene _(-CH 2 -CH 2 -), ethane-1,1-diyl _{(-CH (CH 3) -)} , propylene _{(-CH 2 -CH 2 -CH 2 -} ), 1- methyl - ethylene _{(-CH (CH 3) -CH 2} -), propane-1,1-diyl ( _{- (CH) -CH 2 -CH 3} ), propane-2,2-diyl _{(-C (CH 3) 2 -} ), propylene-1,1-diyl _{(- (- CH) -CH 2} -CH 3) propylene -1,1-3- diyl _{(- (- CH) -CH 2} -CH 2 -), butylene _{(-CH 2 -CH 2 -CH 2 -CH} 2 -), butane-1,1-diyl ( -(-CH) -CH _2- CH _2- CH ₃ ) is included.
Typical unsaturated alkylene groups (ie, alkenylene or alkynylene) are not particularly limited, but are limited to 1-propene-3,3-diyl, 1-propyne-3,3-diyl, 1-butene. -4,4-Zyle, 1-Butyne-4,4-Zyle, 2-Buten-1,4-Zyle, 2-Butyne-1,4-Zyle, 2-Pentene-1,5-Zyle, 3-Pentene -1,5-diyl, 2-pentyne-1,5-diyl, 3-pentyne-1,5-diyl, 3-hexene-1,6-diyl, 3-hexyne-1,6-diyl, 4-hexene Includes -1,6-diyl, and 4-hexyne-1,6-diyl,
Typical saturated or unsaturated cyclic alkylene groups (ie, cycloalkylenes) are not particularly limited, but are not limited to cyclopropane-1,1-diyl, cyclopropane-1,2-diyl, cyclobutane-1. , 1-diyl, cyclobutane-1,3-diyl, cyclopentane-1,1-diyl, cyclopentane-1,3-diyl, cyclohexane-1,1-diyl, cyclohexane-1,2-diyl, cyclohexane-1 , 3-Diyl, Cyclohexane-1,4-Diyl, 1-Cyclopentene-3,5-Diyl, 1-Cyclohexene-3,4-Diyl, 1-Cyclohexene-3,5-Diyl, or 1-Cyclohexene-3, 6-Gile and the like are included.

As used herein, the term "acyclic alkyl" refers to a non-cyclic alkyl (ie, a straight chain or branched chain containing at least one carbon atom). The acyclic alkyl may be completely saturated and may contain an acyclic alkene and / or an alkyne. The acyclic alkyl may be optionally substituted.

The term "alkenyl" refers to a type of alkyl group in which the first two atoms of an alkyl group form a double bond that is not part of an aromatic group. That is, the alkenyl group begins with the atom -C (R) = C (R) -R, where R refers to the rest of the alkenyl group, which may be the same or different. The alkenyl moiety may be branched, linear or cyclic (in this case also known as a "cycloalkenyl" group). Depending on the structure, the alkenyl group can be a monoradical or a diradical (ie, an alkenylene group). The alkenyl group may be optionally substituted. Non-limiting examples of alkenyl groups include -CH = CH ₂ , -C (CH ₃ ) = CH ₂ , -CH = CHCH ₃ , -C (CH ₃ ) = CHCH ₃ . The alkenylene group is not particularly limited, but -CH = CH-, -C (CH ₃ ) = CH-, -CH = CHCH _2- , -CH = CHCH ₂ CH _2- , and -C ( CH ₃ ) = CHCH _2- is included. The alkenyl group can have 2 to 10 carbons. The alkenyl group may also be a "lower alkenyl" having 2 to 6 carbon atoms.

The term "alkynyl" refers to a type of alkyl group in which the first two atoms of an alkyl group form a triple bond. That is, the alkynyl group begins with -C = CR, where R refers to the rest of the alkynyl group, which may be the same or different. The "R" portion of the alkynyl moiety can be branched, linear, or cyclic. Depending on the structure, the alkynyl group can be a monoradical or a diradical (ie, an alkynylene group). The alkynyl group may be optionally substituted. Non-limiting examples of alkynyl groups are not particularly limited, but are not limited to -C≡CH, -C≡CCH ₃ , -C≡CCH ₂ CH ₃ , -C≡C-, and -C≡CCH ₂ −. Is included. The alkynyl group can also have 2-10 carbons. The alkynyl group may also be a "lower alkynyl" having 2 to 6 carbon atoms.

As used herein, the term "ring" refers to a structure closed by any covalent bond. Rings include, for example, carbocycles (eg, aryl and cycloalkyl), heterocycles (eg, heteroaryl and non-aromatic heterocycles), aromatics (eg, aryl and heteroaryl), and non-aromatic (eg, eg, aryl and heteroaryl). Cycloalkyl and non-aromatic heterocycles) are included. The ring can be monocyclic or polycyclic. The ring can optionally be replaced.
As used herein, the term "ring system" refers to one or more rings.
The term "membered ring" may include any cyclic structure. The term "member" means the number of skeletal atoms that make up the ring. Thus, for example, cyclohexyl, pyridine, pyran, and thiopyran are 6-membered rings, and cyclopentyl, pyrrole, furan, and thiophene are 5-membered rings.
The term "condensed" refers to a structure in which two or more rings share one or more bonds.
The term "carbon ring" or "carbon ring" refers to a ring in which each atom forming the ring is a carbon atom. Carbocycles include aryls and cycloalkyls. Thus, the term distinguishes a carbon ring from a heterocycle (“heterocycle”) that contains at least one atom (ie, a heteroatom) whose ring skeleton is different from carbon. Heterocycles include heteroaryls and heterocycloalkyls. Carbocycles and heterocycles can optionally be substituted.

The term "aromatic" refers to a planar ring with a delocalized π-electron system containing 4n + 2n (n is an integer) electrons. Aromatic rings can be formed from 5, 6, 7, 8, 9, or 10 or more atoms. Aromatic compounds can be optionally substituted. The term "aromatic" includes both carbocyclic aryls (eg, phenyl) and heterocyclic aryls (or "heteroaryls" or "heteroaromatics") groups (eg, pyridines). The term includes monocyclic or fused ring polycyclic (ie, rings sharing adjacent carbon atom pairs) groups.

As used herein, the term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. Aryl rings can be formed of 5, 6, 7, 8, 9, or 10 or more carbon atoms. Aryl groups can optionally be substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthalenyl, phenanthrenyl, anthracenyl, fluorenyl, and indenyl. Depending on the structure, the aryl group may be a monoradical or a diradical, in which case it is known as an arylene group. Examples of the arylene group are not particularly limited, but are not limited to benzene-1,3-diyl, benzene-1,4-diyl, naphthalene-2,7-diyl, naphthalene-2,6-diyl, naphthalene-. 1,4-Diyl, naphthalene-1,5-diyl, acenaphthene-diyl, phenanthrene-3,8-diyl, fluoroanthene-diyl and the like are included.

"Aralkyl" means an alkyl group as defined herein, substituted with an aryl group. Non-limiting aralkyl groups include benzyl, phenethyl and the like.

"Aralkenyl" means an alkenyl group as defined herein, substituted with an aryl group.

などが含まれる。構造に依存して、シクロアルキル基は、モノラジカル又はジラジカル（例えば、シクロアルキレン基）であり得る。シクロアルキル基は、３〜７個の炭素原子を有する「低級シクロアルキル」であってもよい。
「シクロアルキルアルキル」は、シクロアルキル基で置換された、本明細書で定義されるアルキル基を意味する。非限定的なシクロアルキルアルキル基には、シクロプロピルメチル、シクロブチルメチル、シクロペンチルメチル、シクロヘキシルメチルなどが含まれる。 The term "cycloalkyl" refers to monocyclic or polycyclic groups that contain only carbon and hydrogen and can be saturated, partially unsaturated, or completely unsaturated. Cycloalkyl groups include groups with 3-10 ring atoms. Examples of cycloalkyl groups are as follows:

Etc. are included. Depending on the structure, the cycloalkyl group can be a monoradical or a diradical (eg, a cycloalkylene group). The cycloalkyl group may be a "lower cycloalkyl" having 3 to 7 carbon atoms.
"Cycloalkylalkyl" means an alkyl group as defined herein substituted with a cycloalkyl group. Non-limiting cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and the like.

The term "heterocycle" refers to heteroaromatic and heteroalicyclic groups containing 1 to 4 heteroatoms selected from O, S, and N, respectively, with each heterocyclic group 4-10 in the ring system. It has a number of atoms, provided that the ring of the group does not contain two adjacent O or S atoms. Here, whenever the number of carbon atoms in a heterocycle (eg, C _{1 to} C ₆ heterocycles) is indicated, at least one other atom (heteroatom) must be present in the ring. Names such as "C _1- C ₆ heterocycles" refer only to the number of carbon atoms in the ring, not the total number of atoms in the ring. It is understood that heterocyclic rings can have additional heteroatoms within the ring. A name such as "4-6 membered heterocycle" refers to the total number of atoms contained within the ring (ie, a 4, 5, or 6 membered ring, where at least one atom is a carbon atom. Yes, at least one atom is a heteroatom and the remaining 2-4 atoms are either carbon atoms or heteroatoms). In a heterocycle having two or more heteroatoms, these two or more heteroatoms may be the same or different from each other. Heterocycles are optionally substituted. The bond to the heterocycle may be heteroatom or mediated by a carbon atom. Non-aromatic heterocyclic groups include groups having only 4 atoms in the ring system, whereas aromatic heterocyclic groups must have at least 5 atoms in the ring system. Heterocyclic groups include a benzo-condensed ring system. An example of a 4-membered heterocyclic group is azetidineyl (derived from azetidine). An example of a 5-membered heterocyclic group is thiazolyl. An example of a 6-membered heterocyclic group is pyridyl and an example of a 10-membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydropyranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, tioxanyl, piperazinyl, azetidinyl, oxetanyl, Thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyranyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3 -Dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanyl, 3H-indrill and quinolidinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, frills, thienyl, isooxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzoimidazolyl, benzofuranyl, cinnolyl. , Indridinyl, phthalazinyl, pyridazinyl, triazinyl, isoindrill, pteridinyl, prynyl, oxadiazolyl, thiadiazolyl, frazanyl, benzoflazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyldinyl, and flopyridinyl. The aforementioned groups derived from the groups listed above may be C-linked or N-linked where possible. For example, the group derived from pyrrole may be pyrrole-1-yl (N-bond) or pyrrole-3-yl (C-bond). In addition, the groups derived from imidazole are imidazole-1-yl or imidazole-3-yl (both N-linked) or imidazole-2-yl, imidazole-4-yl, or imidazole-5-yl (all C). -Combination) may be used. Heterocyclic groups include benzo-condensed ring systems and ring systems substituted with one or two oxo (= O) moieties such as pyrrolidine-2-one. Depending on the structure, the heterocyclic group can be a monoradical or a diradical (ie, a heterocyclene group).

などが含まれる。構造に依存して、ヘテロアリール基は、モノラジカル又はジラジカル（すなわち、ヘテロアリーレン基）であり得る。
ヘテロアリーレン基の例には、特に限定されるものではないが、ピリジンジイル、ピリミジンジイル、ピラジンジイル、フランジイル、チオフェンジイル、キノリンジイル、イソキノリンジイル、ベンゾフランジイル、ベンゾチオフェンジイル、ベンゾオキサゾールジイル、ベンゾチアゾールジイル、及びインドールイルが含まれる。ヘテロアリーレン基の具体的な例には、特に限定されるものではないが、フラン−２，５−ジイル、チオフェン−２，４−ジイル、１，３，４−オキサジアゾール−２，５−ジイル、1、３，４−チアジアゾール−２，５−ジイル、１，３−チアゾール−２，４−ジイル、１，３−チアゾール−２，５−ジイル、ピラゾール−３，４−ジイル、ピリジン−２，３−ジイル、ピリジン−２，４−ジイル、ピリジン−２，５−ジイル、６−メチル−ピリジン−２，５−ジイル、ピリジン−２，６−ジイル、ピリミジン−２，４−ジイル、ピリミジン−２，５−ジイル、キノリン−２，３−ジイル、ピリダジン−ジイル、トリアジン−ジイルなどが含まれる。 The term "heteroaryl" or alternative "heteroaromatic" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. The N-containing "complex aromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. Examples of heteroaryl groups are as follows:

Etc. are included. Depending on the structure, the heteroaryl group can be a monoradical or a diradical (ie, a heteroarylene group).
Examples of heteroarylene groups are not particularly limited, but are not limited to pyridinediyl, pyrimidinediyl, pyrazinediyl, frangyl, thiopheneyl, quinolinediyl, isoquinolinediyl, benzofurandiyl, benzothiopheneyl, benzoxazolediyl, benzothiazolediyl. , And indole il. Specific examples of the heteroarylene group are not particularly limited, but are not limited to furan-2,5-diyl, thiophene-2,4-diyl, 1,3,4-oxadiazole-2,5-. Diyl, 1,3,4-thiazole-2,5-diyl, 1,3-thiazole-2,4-diyl, 1,3-thiazole-2,5-diyl, pyrazole-3,4-diyl, pyridine- 2,3-Zyl, Pyridine-2,4-Zyl, Pyridine-2,5-Zyl, 6-Methyl-Pyridin-2,5-Dyl, Pyridine-2,6-Zyl, Pyrimidine-2,4-Zyl, Includes pyrimidine-2,5-diyl, quinoline-2,3-diyl, pyridazine-diyl, triazine-diyl and the like.

などが含まれる。複素脂環式という用語はまた、特に限定されるものではないが、単糖類、二糖類、及びオリゴ糖を含む、すべての環形態の炭水化物を含む。構造に依存して、ヘテロシクロアルキル基は、モノラジカル又はジラジカル（すなわち、ヘテロシクロアルキレン基）であり得る。ヘテロシクロアルキレン基の非限定例には、ピロリジン−ジイル、ピペリジン−ジイル、モルホリン−ジイル、ピペラジン−ジイル、テトラヒドロピラン−ジイル、２−オキソピペリジン−ジイル、又はチオモルホリン−ジイルなどが含まれる。 As used herein, the term "non-aromatic heterocycle", "heterocycloalkyl", or "heterocyclic" refers to a non-aromatic ring in which one or more atoms forming the ring are heteroatoms. Point to. A "non-aromatic heterocycle" or "heterocycloalkyl" group refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. This group may be condensed with aryl or heteroaryl. The heterocycloalkyl ring can be formed by 3, 4, 5, 6, 6, 7, 8, 9, or 10 or more atoms. The heterocycloalkyl ring may be optionally substituted. In certain embodiments, the non-aromatic heterocycle may contain one or more carbonyl or thiocarbonyl groups, such as oxo and thio-containing groups. Examples of heterocycloalkyl are not particularly limited, but are limited to lactam, lactone, cyclic imide, cyclic thioamide, cyclic carbamate, tetrahydropyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1 , 3-Dioxane, 1,4-Dioxane, 1,4-Dioxane, Piperazin, 1,3-Oxazolidine, 1,4-Oxazolidine, 1,4-Oxazolidine, Tetrahydro-1,4-Thiadin, 2H-1,2 -Oxazolidine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydropyran, tetrahydrofuran, pyrrolidine, pyrrolidine, Pyrrolidine, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxoran, 1,3-dithiol, 1,3-dithiolan, isoxazolidine, isooxazolidine, oxazolidine, oxazolidine, oxazolidinone, thiazolin, thiazolidine, And 1,3-oxathiolane. Examples of heterocycloalkyl groups, also called non-aromatic heterocycles:

Etc. are included. The term complex alicyclic also includes, but is not limited to, all ring forms of carbohydrates, including monosaccharides, disaccharides, and oligosaccharides. Depending on the structure, the heterocycloalkyl group can be a monoradical or a diradical (ie, a heterocycloalkylene group). Non-limiting examples of heterocycloalkylene groups include pyrrolidine-diyl, piperidine-diyl, morpholine-diyl, piperazine-diyl, tetrahydropyran-diyl, 2-oxopiperidine-diyl, thiomorpholine-diyl and the like.

The term "halo" or "halogen" or alternative "halide" means fluoro, chloro, bromo, and iodine.

The terms "haloalkyl", "haloalkenyl", "haloalkynyl", and "haloalkoxy" include alkyl, alkenyl, alkynyl, and alkoxy structures in which at least one hydrogen is substituted with a halogen atom. In a particular embodiment in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are all the same as each other. In other embodiments, where two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are not all the same.

As used herein, the term "fluoroalkyl" refers to an alkyl group in which at least one hydrogen is substituted with a fluorine atom. Examples of fluoroalkyl groups include, but are not limited to, -CF ₃ , -CH ₂ CF ₃ , -CF ₂ CF ₃ , -CH ₂ CH ₂ CF _{3, and the} like.

As used herein, the terms "heteroalkyl,""heteroalkenyl," and "heteroalkynyl" mean that one or more skeletal chain atoms are heteroatoms (eg, oxygen, nitrogen, sulfur, silicon, phosphorus, or theirs. Includes optionally substituted alkyl, alkenyl, and alkynyl groups). The heteroatom may be located at any internal position of the heteroalkyl group, or at a position where the heteroalkyl group is attached to the rest of the molecule. The examples are not particularly limited, but are not particularly limited, but are −CH ₂ −O _{−CH 3} , −CH ₂ −CH ₂ −O−CH ₃ , −CH ₂ −NH _{−CH 3} , −CH ₂ −CH ₂ −. NH-CH ₃ , -CH _2- N (CH ₃ ) -CH ₃ , -CH _{2 -CH 2-} NH-CH ₃ , -CH _{2 -CH 2-} N (CH ₃ ) -CH ₃ , -CH _2- S-CH _{2 -CH 3} , -CH _2- CH ₂ , -S (O) -CH ₃ , -CH _2- CH _2- S (O) _{2 -CH 3} , -CH = CH-O-CH ₃ , -Si (CH ₃ ) ₃ , -CH _2- CH = N-OCH ₃ , and -CH = CH-N (CH ₃ ) -CH ₃ are included. Further, a maximum of two heteroatoms may be continuous, for example, -CH _2- NH-OCH ₃ and -CH _2- O-Si (CH _{3) 3.}
The term "heteroatom" refers to an atom other than carbon or hydrogen. Heteroatoms are typically independently selected from, but not limited to, oxygen, sulfur, nitrogen, silicon, and phosphorus. In an embodiment in which two or more heteroatoms are present, the two or more heteroatoms may all be the same as each other, and some or all of the two or more heteroatoms may be different from each other. ..

The term "bond" or "single bond" refers to a chemical bond between two atoms, or a chemical bond between two parts if the atoms connected by the bond are considered to be part of a larger partial structure. Point to.

The "alkoxy" group refers to the —O (alkyl) group, where alkyl is as defined herein. Non-limiting examples of the alkoxy group include, but are not limited to, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like.

"Hydroxyalkyl" refers to an alkyl group as defined herein, substituted with at least one hydroxy group. Non-limiting examples of hydroxyalkyl are not particularly limited, but hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-. Hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1- (hydroxymethyl) -2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, and 2-( Hydroxymethyl) -3-hydroxypropyl is included.

"Alkoxyalkyl" refers to an alkyl group as defined herein, substituted with an alkoxy group as defined herein.

The "alkenyloxy" group means the —O (alkenyl) group, where alkenyl is as defined herein.

The "aryloxy" group refers to the -O (aryl) group, where aryl is as defined herein.

The term "amino" _{means two} -NH groups.

The term "alkylamino" or "alkylamine" refers to the group -NHR ^20, wherein, R ²⁰ represents an alkyl group, as defined herein. The alkylamino group may or may not be substituted. Non-limiting examples of dialkylamino groups include methylamino, ethylamino, propylamino, isopropylamino, butylamino, butto-3-enylamino, [(Z) -but-2-enyl] -methyl-amino, hexylamino and the like. Is included.

The term "dialkylamino" or "dialkylamine" refers to the group -NR ²¹ R ²² where each R ²¹ and R ²² group is independently defined as alkyl, cycloalkyl, aryl, herein. It is a cycloheteroalkyl or heteroaryl group. In certain embodiments, the R ²¹ and R ²² groups can be combined with the N atoms to which they are attached to form a cyclic ring system, particularly a 5- or 6-membered nitrogen-containing heterocycle. The dialkylamino group may or may not be substituted. Non-limiting examples of dialkylamino groups include dimethylamino, diethylamino, ethyl (methyl) amino, butyl (ethyl) amino, 1-butenyl (ethyl) amino, [(Z) -but-2-enyl] -methyl-amino. , Dibutylamino, hexyl (methyl) amino, cyclopentyl (methyl) amino, cyclopent-2-ene-1-yl (methyl) amino, morpholino, methylpiperazino and the like.

The term "arylamino" or "arylamine" refers to the -NR ²³ R ²⁴ group, where R ²³ is the aryl as defined herein and the R ²⁴ group is hydrogen, as defined herein. It is an alkyl, cycloalkyl, aryl, cycloheteroalkyl, or heteroaryl group. Arylamino groups may or may not be substituted. Non-limiting examples of arylamino groups include phenylamino, trillamino, 3-methoxyphenylamino, 4-phenylphenylamino, 4-trifluoromethylphenylamino, 3-methoxyphenyl (methyl) amino, 2-fluoromethylphenylamino. , And 3-Phenylphenylamino and the like.

The term "heteroarylamino" or "heteroarylamine" refers to the -NR ²⁵ R ²⁶ group, where R ²⁵ is the heteroaryl as defined herein and the R ²⁶ group is hydrogen, herein. Alkyl, cycloalkyl, aryl, cycloheteroalkyl, or heteroaryl group as defined in. The heteroarylamino group may or may not be substituted. Non-limiting examples of heteroarylamino groups include pyrimidin-2-yl-amino, pyrimidin-4-yl-amino, pyrimidin-5-yl-amino, and (6-methylpyrimidine-2-yl) amino (4,6). -Dimethylpyrimidine-2-yl), (4-fluoro-6-methyl-pyrimidine-2-yl) amino, (4-methoxy-6-methyl-pyrimidine-2-yl) amino, (4-cyanopyrimidine-2) -Il) amino, [4- (trifluoromethyl) pyrimidin-2-yl] amino, [4- (dimethylamino) -5-fluoro-pyrimidine-2-yl] amino, [4- (3-pyridyl) pyrimidin -2-yl] amino, [4- (3,5-dimethylpyrazole-1-yl) pyrimidin-2-yl] amino, [4- (3,5-dimethylpyrazole-1-yl) -6-methyl- Pyrimidin-2-yl] amino, [4- (2,4-dimethylthiazole-5-yl) pyrimidin-2-yl] amino, [4- (2-methyl-1,2,4-triazole-3-yl) ) Pyrimidin-2-yl] amino, 6- (1-methylpyrazole-4-yl) -2-pyridyl] amino, [6- (4-cyclopropyl-1,2,4-triazole-3-yl)- 2-Pyridyl] amino, [6-4-isopropyl-1,2,4-triazole-3-yl] -2-pyridyl] amino, [2- (3-pyridyl) pyrimidin-4-yl] amino, [5 -Cyano-2- (3-pyridyl) pyrimidin-4-yl] amino, (6-fluoro-2-morpholino-pyrimidine-4-yl) amino, (4,6-dimethylflo [2,3-d] pyrimidin- 2-yl) amino, (6-methylflo [2,3-d] pyrimidin-2-yl) amino, 1H-pyrazole-5-yl-amino, 1H-pyrazole-4-yl-amino, flo [2,3 -D] Pyrimidine-2-yl-amino, pyridine-2-yl-amino, pyridine-3-yl-amino, or pyridine-4-yl-amino are included.

"Alkylaminoalkyl" refers to an alkyl group as defined herein, substituted with an alkylamine as defined herein.

The term "acylamino" refers to the group -N (R ²⁷ ) -C (= O) R ²⁸ , where R ²⁷ is hydrogen or an alkyl as defined herein and R ²⁸ is hydrogen, herein. Alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroalkyl, heteroarylalkyl, aryl, or heteroaryl as defined in. Depending on the structure, the acylamino group may also be known as an alkylcarbonylamino, arylcarbonylamino, or heteroarylcarbonylamino. The acylamino group may or may not be substituted. Non-limiting examples of acylamino groups include formylamino, acetylamino, acetyl (methyl) amino, cyclohexylcarbonylamino, cyclohexylmethylcarbonylamino, benzylcarbonylamino, methyl (benzylcarbonyl) amino, benzoylamino, benzoyl (methyl) amino, Includes (3-methoxybenzoyl) -methyl-amino, (4-methoxypyridine-2-carbonyl) -amino, pyridine-2-carbonylamino, pyridine-2-carbonyl (methyl) amino and the like.

The term "aminocarbonyl" refers to the group -C (= O) NR ²⁹ R ³⁰ , where R ²⁹ and R ³⁰ are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl as defined herein. , Heterocycloalkyl, arylalkyl, heteroalkyl, heteroarylalkyl, aryl, or heteroaryl. In certain embodiments, the R ²⁹ and R ³⁰ groups can be combined with the N atoms to which they are attached to form a cyclic ring system, particularly a 5- or 6-membered nitrogen-containing heterocycle. .. Depending on the structure, the aminocarbonyl group may also be known as alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl. The aminocarbonyl group may or may not be substituted. The aminocarbonyl group may also be known as carbamoyl. Non-limiting examples of aminocarbonyl groups include aminocarbonyl (-C (= O) NH ₂ ), dimethylaminocarbonyl, 2-hydroxyethylaminocarbonyl, 2-methoxyethylaminocarbonyl, 2-dimethylaminoethylaminocarbonyl, benzyl. Aminocarbonyl, phenylaminocarbonyl, phenyl (methyl) aminocarbonyl, trill (methyl) aminocarbonyl, piperidine-1-carbonyl, morpholin-4-carbonyl, 4-methylpiperazin-1-carbonyl, pyrimidine-2-yl-aminocarbonyl , 1H-pyrazole-5-yl-aminocarbonyl and the like.

The "acylamino" and "aminocarbonyl" groups are chemically amide moieties. The amide moiety can form a bond between the amino acid or peptide molecule and the compounds described herein, thereby forming a prodrug. Any amine or carboxyl side chain on the compounds described herein can be amidated. Procedures and specific groups for producing such amides are known to those of skill in the art, Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and. It is found in literature such as Benoiton N. Leo, Chemistry of Peptide synthesis, CRC Press 2005, which are incorporated herein by reference in their entirety.

"Carboxy" means a -C (= O) -OH group.

The term "acyl" refers to the group -C (= O) -R ³¹ , where R ³¹ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl as defined herein. Alkyl, heteroalkyl, heteroarylalkyl, aryl, or heteroaryl. The acyl group may or may not be substituted. Non-limiting examples of acyl groups include acetyl, propanoyl, hexanoyl, octanoyl, decanoyl, benzoyl, pyridine-3-carbonyl, 4-methoxybenzoyl, 2,2,2-trifluoroacetyl, 2-hydroxyacetyl, 9,9. , 10,10,10-pentafluorodecanoyl, 2- (2-hydroxyethoxy) acetyl and the like.

The term "alkoxycarbonyl" refers to the group -C (= O) -OR ³² , where R ³² is an alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, hetero as defined herein. It is an alkyl or a heteroarylalkyl. The alkoxycarbonyl group may or may not be substituted. Non-limiting examples of alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, allyloxycarbonyl, 2-hydroxyethoxycarbonyl, 2-methoxyethoxycarbonyl, 2-dimethylaminoethoxycarbonyl, 3- (dimethylamino) propoxy. Includes carbonyl, benzyloxycarbonyl, 2- (3-methoxyphenyl) ethoxycarbonyl, 2-morpholinoethoxycarbonyl and the like.

The term "aryloxycarbonyl" refers to the group -C (= O) -OR ³³ , where R ³³ is the aryl as defined herein. The aryloxycarbonyl group may or may not be substituted.

The term "heteroaryloxycarbonyl" refers to the group -C (= O) -OR ³⁴ , where R ³⁴ is the heteroaryl as defined herein. The heteroaryloxycarbonyl group may or may not be substituted.

The term "acyloxy" refers to the group-OC (= O) -R ³¹ groups, where R ³¹ is as defined herein. The acyloxy group may or may not be substituted.

Alkoxycarbonyls, aryloxycarbonyls, heteroaryloxycarbonyls, and acyloxy groups belong to a family of functional groups known as "ester" groups. Procedures (eg, esterification reactions) and specific groups for producing esters (ie, alkoxycarbonyls, aryloxycarbonyls, heteroaryloxycarbonyls, or acyloxy groups) are known to those of skill in the art, such as Greene and Wuts,. It is found in literature such as Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999 (which is incorporated herein by reference in its entirety). Any hydroxy or carboxyl side chain on the compounds described herein can be esterified.

The term "aminocarbonylamino" refers to the group -N (R ²⁷ ) -C (= O) -NR ²⁹ R ³⁰ , where R ²⁷ , R ²⁹ , and R ³⁰ are independent herein. It is defined in. The aminocarbonylamino group may or may not be substituted.

The term "aminocarbonyloxy" refers to the group -OC (= O) -NR ²⁹ R ³⁰ , where R ²⁹ and R ³⁰ are as defined above. The aminocarbonyloxy group may or may not be substituted.

The term "alkoxycarbonylamino" refers to the group -N (R ²⁷ ) -C (= O) -OR ³⁵ , where R ²⁷ is defined above and R ³⁵ is defined herein. Alkoxy, alkoxy, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroalkyl, or heteroarylalkyl. The alkoxycarbonylamino group may or may not be substituted. Representative examples of the alkoxycarbonylamino group are, but are not limited to, tert-butoxycarbonylamino or 9H-fluorene-9-yloxycarbonylamino.

The term "aryloxycarbonylamino" refers to the group -N (R ²⁷ ) -C (= O) -OR ³⁶ , where R ²⁷ is as defined above and R ³⁶ is the aryl as defined herein. Is. The aryloxycarbonylamino group may or may not be substituted.

The term "heteroaryloxycarbonylamino" refers to the group -N (R ²⁷ ) -C (= O) -OR ³⁷ , where R ²⁷ is as defined above and R ³⁷ is defined herein. It is a heteroaryl to be. The heteroarylalkoxycarbonylamino group may or may not be substituted.

As used herein, the terms "part", "chemical part", "group", and "chemical group" refer to a particular segment or functional group of a molecule. A chemical moiety is often a recognized chemical entity embedded in or attached to a molecule.

The term "sulfonyl" means the divalent group −S (= O) ₂₋ . The “substituted sulfonyl” group refers to the group −S (= O) _2- R ³⁸ , where R ³⁸ is an alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl as defined herein. , Heteroalkyl, heteroarylalkyl, aryl, or heteroaryl.

The term "aminosulfonyl" or "sulfonamide" refers to the group -S (= O) ₂ NH ₂ . "Substituted aminosulfonyl" or "substituted sulfonamide" refers to the group -S (= O) ₂ NR ²⁹ R ³⁰ , where R ²⁹ and R ³⁰ are independently as described herein. be.

The term "sulfonylamino" means and includes a sulfonyl group attached to the ^{amino group -N (R 27} ) -S (= O) ₂ R ^{38 , where R 27} and R ³⁸ are independent of each other. As described herein. The sulfonylamino group may or may not be substituted.

The term "sulfo" refers to -S (= O) ₂ OH. The “substituted sulfonyl” group refers to the group −S (= O) ₂ OR ³¹ , where R ³¹ is as defined above.

The term "sulfinyl" refers to two groups-S (= O)-. “Substituent sulfinyl” refers to −S (= O) R ³⁸ , where R ³⁸ is any substituent as defined herein.

The term "sulfanyl" refers to the divalent group -S-. "Substituent sulfanyl" refers to a group such as ^{-SR 38 , where R 38} is any substituent as defined herein. Non-limiting examples of substituted sulfanyl groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, gnat-3-enylsulfonyl, hexylthio, benzylthio, phenylthio, (3-methoxyphenyl) sulfanyl, or 2-Pyridylsulfanyl is included.

As used herein, the term "thiol" refers to group-SH.

As used herein, the term "hydroxyl" refers to the group -OH.

As used herein, the term "carbonyl" refers to the divalent group −C (= O) −.

The "isocyanate" group refers to the -N = C = O group.

The "isothiocyanate" group refers to the -N = C = S group.

As used herein, the term "trihalomethanesulfonyl" _{refers to a group of formula-S (= O) 2-} CX ₃ , where X is a halogen.

As used herein, the term "cyano" refers to the group of formula-CN.

"Cyanoalkyl" means an alkyl group as defined herein substituted with at least one cyano group.

The terminology used herein "azido" refers to the group -N _3.

As used herein, the term "nitro" refers to _{group -NO 2.}

As used herein, the term "O-thiocarbamil" refers to the group of _{formula-OC (= S) NR 2.}

As used herein, the term "N-thiocarbamyl" refers to the group of formula-N (H) -C (= S) OR.

The term "substituted" or "possibly substituted" means that the referenced group is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroalkyl, cycloalkylalkyl, heterolipid ring. Formula, heterocycloalkyl, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfon, arylsulfone, cyano, halo, acyl, nitro, haloalkyl, fluoroalkyl, mono- and di-substituted amino groups. It may be substituted with one or more additional groups individually and independently selected from aminos, including aminos, and these protected derivatives. For example, any substituent may be L ⁿ R ⁿ ', where each L ⁿ is a bond, −O−, −C (= O) −, −S−, −S (= O) −, −S. (= O) _2- , -NH-, -NHC (O)-, -C (O) NH-, S (= O) ₂ NH-, -NHS (= O) ₂ , -OC (O) NH- , -NHC (O) O-,-(substituted or unsubstituted C _{1 to} C ₆ alkyl), or-(substituted or unsubstituted C _{2 to} C ₆ alkenyl); each R ^n'is selected independently. It is independently selected from H, (substituted or unsubstituted C _{1 to} C ₄ alkyl), (substituted or unsubstituted C _{3 to} C ₆ cycloalkyl), heteroaryl, or heteroalkyl. Protecting groups capable of forming protective derivatives of the above substituents are known to those of skill in the art and are found in references such as the above Greene and Wuts.

Other Definitions Some other terms or phrases used herein are defined below.
-The term "acceptable" or "pharmaceutically acceptable" with respect to a substance such as a salt, carrier, excipient, or diluent used herein, or a formulation, composition, or ingredient is a treatment. That there is no lasting adverse effect on the general health of the subject being subjected to, or that it does not negate the biological activity or properties of the compound and is relatively non-toxic, i.e. the material, formulation, said. It means that the composition, or ingredient, can be administered to a subject without causing undesired biological effects or interacting with any of the ingredients of the composition in which it is contained in a detrimental manner. do.
-The term "prodrug" as used herein is converted to an active or more active species via several processes, such as conversion by metabolic pathways, after administration to an individual and subsequent absorption. Refers to a drug precursor. That is, the term includes any derivative of a compound that, when administered to a recipient, can directly or indirectly provide the compound of the invention or a pharmaceutically active metabolite or residue thereof. Some prodrugs have a chemical group on the prodrug that makes it less active and / or imparts solubility or certain other properties to the drug. Once the chemical group is cleaved and / or modified from the prodrug, an active drug is produced. Prodrugs are often useful because they can be easier to administer than the parent drug in some circumstances. These may be biologically available, for example by oral administration, but not the parent drug. Particularly preferred derivatives or prodrugs provide the bioavailability of the compounds of the invention when such compounds are administered to an individual (eg, by allowing the orally administered compound to be more easily absorbed into the blood). Derivatives that increase or enhance delivery of the parent compound to the biological compartment (eg, brain, or lymphatic system).
-The term "solvate" means the compounds of the invention described herein further comprising a stoichiometric or non-stoichiometric solvent bound by a non-covalent intermolecular force. In some embodiments, the solvate may be formed during a crystallization process using a solvent such as water, ethanol. Non-limiting examples of solvates include hydrates that can be formed when the solvent is water and alcoholates which can be formed when the solvent is an alcohol.
-The term "pharmaceutically acceptable salt" as used herein retains the biological effectiveness of the free acids and bases of a particular compound and is not biologically or otherwise undesirable. It means no salt. The compounds described herein can have acidic or basic groups and thus react with some inorganic or organic bases and any of the inorganic and organic acids to form pharmaceutically acceptable salts. be able to. These salts were thus formed during the final isolation and purification of the compounds of the invention, or by reacting the purified compound in its free base form separately with a suitable organic or inorganic acid. By isolating the salt, it can be prepared in-situ.
-The terms "treating,""treating," or "treating," as used herein, and other grammatical equivalents alleviate a disease or condition, or one or more symptoms thereof. Relieving or ameliorating, preventing additional symptoms, preventing the underlying metabolic causes of the disease, controlling the disease or condition, eg stopping the progression of the disease or condition, the disease or condition It is intended to include prevention, including alleviating, causing regression of the disease or condition, alleviating the symptoms caused by the disease or condition, or stopping the symptoms of the disease or condition. The term further includes achieving therapeutic and / or prophylactic benefits. Therapeutic benefit means eradication or amelioration of the underlying disease being treated. Also, even though the individual still suffers from the underlying disorder, eradication or amelioration of one or more physiological symptoms associated with the underlying disease achieves therapeutic benefit and improves in the individual. Observed. For prophylactic benefit, the composition is an individual at risk of developing a particular disease, or an individual who reports one or more of the physiological symptoms of the disease even though the disease has not been diagnosed. Is administered to.
-The terms "prevent,""prevent," and "prevention" are methods of delaying and / or eliminating the onset of a disorder, disease, or condition, and / or associated symptoms, subject disability, It means including a method of preventing the acquisition of a disease or condition, or a method of reducing a subject's risk of acquiring a disorder, disease or condition.
-The term "inhibiting, inhibiting, and / or delaying" is intended to refer to the object of the invention as follows: "partially or completely inhibiting, inhibiting, and / or delaying". In this case, measuring and determining such inhibition, inhibition, and / or delay by conventional measurement and determination methods is within the expertise of the average person skilled in the art. Thus, for example, partial inhibition, inhibition, and / or delay can be measured and determined in relation to complete inhibition, inhibition, and / or delay.
-The terms "subject" and "patient" as used herein are used interchangeably to refer to an individual being treated for a proliferative disorder such as cancer or anon-neoplastic state. In a specific embodiment, the individual is a primate, more specifically a human. In another embodiment, the individual is, but is not limited to, a cow, a pig, a sheep, a goat, a horse, a dog, a cat, a rabbit, a rat, and a mouse.
-The terms "patient,""subject," or "individual" are used interchangeably. As used herein, these refer to individuals suffering from a disease, specifically a disease associated with a disease associated with abnormal cell proliferation (eg, cancer or non-neoplastic disease). , Mammalian and non-mammalian. Neither term requires an individual to be cared for and / or supervised by a healthcare professional. Mammals are any member of the Mammalian class and are not particularly limited; humans, non-mammals such as chimpanzees, and other apes and monkey species; farm animals such as cows, horses, sheep. , Goats, pigs; domestic animals such as rabbits, dogs, and cats; experimental animals including rodents such as rats, mice, and guinea pigs. Examples of non-mammals include, but are not limited to, birds, fish and the like. In some embodiments of the methods and compositions provided herein, the individual is a mammal. In a preferred embodiment, the individual is human.
-The terms "proliferative disorders" and "proliferative disorders" refer to disorders associated with abnormal cell proliferation such as cancer or dysplasia. Proliferative disorders can be benign or malignant proliferative disorders, such as benign prostatic hyperplasia or neoplastic disorders, preferably malignant proliferative disorders such as cancers, such as solid tumors, particularly advanced solid tumors.
-The terms "tumor,""neoplasm," and "neoplasmic disorder or disease" are used interchangeably herein and cause multicellular organisms to be injured (ie, discomfort or reduced life expectancy). It is meant to refer to unwanted cell proliferation of one or more subsets of cells in a multicellular organism. In certain embodiments, the tumor can be benign (non-cancerous) or malignant (cancerous), including precancerous lesions.
-The term "cancer" means to refer to malignant neoplasms, which are characterized by disordered cell proliferation in which cells have lost the normal regulatory controls that would otherwise govern cell proliferation rates. These randomly dividing cells can spread throughout the body and invade normal tissues in a process called "metastasis."
-The term "neoplasm" means a cell with an abnormal condition or condition characterized by the ability for autonomous proliferation, ie rapidly growing cell proliferation. Neonatal disease states can be classified as pathological, i.e., characterizing or constituting the disease state, or non-pathological, i.e., deviant from normal but not related to the disease state. can do. The term is meant to include any type of cancerous growth or carcinogenic process, metastatic tissue, or malignantly transformed cells, tissues, or organs, regardless of histopathological type or invasive stage. ..
-The term "inhibits tumor proliferation" and its grammatical equivalents refer to any mechanism that can inhibit aberrant cell proliferation. In certain embodiments, the abnormal cell proliferation is inhibited by slowing the proliferation of the abnormal cells. In certain embodiments, the growth of abnormal cells is inhibited by stopping the growth of abnormal cells such as cancer cells. In certain embodiments, tumor cell proliferation is inhibited by killing abnormal cells such as cancer cells. In certain embodiments, the proliferation of abnormal cells is inhibited by inducing apoptosis of abnormal cells such as cancer cells. In certain embodiments, the proliferation of abnormal cells is inhibited by preventing the migration of abnormal cells. In certain embodiments, the proliferation of abnormal cells is inhibited by preventing the infiltration of abnormal cells such as cancer cells.
-The term "cancer stem cell (CSC)" as used herein is a cancer cell having characteristics associated with normal stem cells, specifically the ability to produce all cell types found in a particular cancer sample. Refers to (found in tumors or hematological cancers). CSCs can generate tumors through a stem cell process of self-renewal and differentiation into multiple cell types. In more recent literature, the early term "cancer stem cell" has been replaced by the term "tumor stem-like cell" or "tumor-initiating cell". That is, the term "tumor stem-like cell" or "tumor-initiating cell" is essentially synonymous with "cancer stem cell".
-The term "radiation therapy", "radiotherapy treatment", or "radiotherapy" refers to internal and external radiation therapy, multiple types of radiation therapy, including radiation immunotherapy, as well as various types. Refers to the use of types of radiation (multiple types of radiation, including X-rays, gamma rays, alpha particles, beta particles, photons, electrons, neutrons, radioactive isotopes, and other forms of ionizing radiation). Preferably, radiation therapy involves the use of x-rays.
-The term "pharmaceutical composition" as used herein is not particularly limited, but includes carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, excipients and the like. Refers to a biologically active compound, optionally mixed with at least one pharmaceutically acceptable chemical component.
-The terms "pharmaceutically acceptable carrier", "pharmaceutically acceptable excipient", "Physiologically acceptable carrier", or "Physiologically acceptable excipient" are liquids, Alternatively, it refers to a pharmaceutically acceptable material, composition, or vehicle, including a solid packing material, a diluent, a solvent, or an encapsulating material. In one embodiment, each ingredient is compatible with the other ingredients of the pharmaceutical formulation and is overly toxic, irritating, allergic, immunogenic, or problematic or complications, commensurate with a reasonable benefit / risk ratio. It is "pharmaceutically acceptable" in the sense that it is suitable for use in contact with human or animal tissues or organs without disease. Remington: The Science and Practice of Pharmacy, 22th ed .; Lippincott Williams & Wilkins: Philadelphia, Pa., 2012; the Handbook of Pharmaceutical Excipients, 6th edition, Rowe et al., Eds., American Pharmaceuticals Association (2011); The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed .; Ash and Ash Eds .; Gower Publishing Company: 2007; and Pharmaceutical Preformulation and Formulation, 2nd ed .; Gibson Ed .; CRC Press LLC: Boca See Raton, Fla., 2009.
-The terms "pharmaceutical combination,""implementation of additional therapy,""administration of additional therapeutic agents," etc., used herein refer to pharmaceutical therapy resulting from a mixture or combination of two or more active ingredients, which are active. Includes both fixed and non-fixed combinations of ingredients. The term "fixed combination" means that at least one of the compounds described herein and at least one adjunct are administered to an individual simultaneously in a single entity or form of administration. The term "unfixed combination" means that at least one of the compounds described herein and at least one adjunct are administered simultaneously as separate entities or consecutively within a variable intervention time limit. Such administration provides effective levels of two or more compounds in an individual's body. These are also applied to cocktail therapies, such as administration of three or more active ingredients.
-The terms "administer", "administering", "administer" and the like as used herein refer to methods that can be used to deliver a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral, duodenal, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical, and rectal. Includes administration. Those of skill in the art are familiar with dosing techniques that can be used with the compounds and methods described herein. In a preferred embodiment, the compounds and compositions described herein are orally administered.
-The terms "co-administration", "administered in combination", and their grammatical equivalents, as used herein, include administration of the selected therapeutic agent to a single individual. That means that the agent comprises a therapeutic prescription that is administered by the same or different routes of administration, or at the same time or at different times. In some embodiments, the compounds described herein are co-administered with other agents. These terms include administration of two or more agents to an animal so that both agents and / or their metabolites are present in the animal at the same time. These include simultaneous administration in separate compositions, administration at different times in separate compositions, and / or administration in compositions in which both agents are present. Thus, in some embodiments, the compounds of the invention and other agents are administered in a single composition. In some embodiments, the compounds of the invention and other agents are mixed in the composition.
-The term "active ingredient", "active substance", or "active agent" alone to a subject to treat, prevent, or ameliorate one or more symptoms of a condition, disorder, or disease. Refers to a compound or pharmaceutical composition thereof administered in combination with or in combination with one or more pharmaceutically acceptable excipients. As used herein, the "active ingredient" and "active substance" can be optically active isomers of the compounds described herein.
-The terms "drug", "therapeutic agent", and "chemotherapeutic agent" are compounds or compounds administered to a subject to treat, prevent, or ameliorate one or more symptoms of a condition, disorder, or disease. Refers to the pharmaceutical composition.
-The term "contacting" or "contacting" refers to bringing together a therapeutic agent and a cell or tissue so that such contact results in a physiological and / or chemical effect. means. Contact can be in vitro, ex vivo, or in vivo. In one embodiment, the therapeutic agent contacts the cells in the cell culture (in vitro) to determine the effect of the therapeutic agent on the cells. In another embodiment, contact of a therapeutic agent with a cell or tissue comprises administration of the therapeutic agent to a subject having the cell or tissue to be contacted.
-The term "effective amount,""therapeutically effective amount," or "medically effective amount," as used herein, is at least administered that relieves to some extent one or more symptoms of the disease or condition being treated. Refers to a sufficient amount of one drug or compound. The result can be a reduction and / or alleviation of signs, symptoms, or causes of the disease, or any other desired modification of the biological system. For example, an "effective amount" for therapeutic use is the amount of composition comprising the compounds disclosed herein necessary to provide a clinically significant reduction in disease. The appropriate "effective" amount may vary from individual to individual. The appropriate "effective" amount for an individual case can be determined using techniques such as dose escalation studies.
-The term "composition", such as in pharmaceutical compositions for the purposes of the present invention, refers to a product comprising an active ingredient and an inert ingredient constituting a carrier, as well as a combination or combination of any two or more ingredients. Intended to include any product that results directly or indirectly from embodied or aggregated, or from the dissociation of one or more components, or from other types of reactions or interactions of one or more components. Will be done. Accordingly, the pharmaceutical composition of the present invention includes any composition prepared by mixing the compound of the present invention with a pharmaceutically acceptable carrier.
- IC ₅₀ or EC _50, as used herein, induced by the particular test compound, inducing, or enhancing at 50% of maximal expression of a particular response, a particular test compound that elicits a dose-dependent response Refers to the dose, concentration, or amount of.
-The term "about" or "approximately" means an acceptable error for a particular value as determined by one of ordinary skill in the art, which in part depends on how the value is measured or determined. do. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" is 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4% of a value or range. Within 3, 2%, 1%, 0.5%, or 0.05%.

-It should be understood that the expressions and terms used herein are for illustration purposes only and should not be considered limiting. "Including," "comprising," or "having," as used herein, and variations thereof are meant to include the items listed below and their equivalents as well as additional items.

II. The compound of the compound formula (I) of the present invention, a pharmaceutically acceptable salt thereof, a hydrate, a solvate, a prodrug, a polymorph, a tautomer, an isotope variant, and a stereoisomer are the present. Described in the specification.

で示される化合物、又はその医薬的に許容し得る塩、水和物、溶媒和物、もしくはプロドラッグ、又はその同位体変異体、互変異性体、もしくは立体異性体に属する。 The compounds of the present invention generally have the formula (I) :.

It belongs to the compound represented by, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, or an isotope variant, tautomer, or stereoisomer thereof.

In the present invention, m is 0, 1, 2, 3, or 4.

In the present invention, d is an integer from 0 to 6, where d is 0, 1, or 2 independently when m is 0; d is 0 independently when m is 1. 1, 2, or 3; if m is 2, d is 0, 1, 2, 3, or 4 independently; if m is 3, d is 0, 1 independently. If 2, 3, 4, or 5, or m is 4, d is independently 0, 1, 2, 3, 4, 5, or 6.

^{L 1} of the present invention is a single bond, alkylene, alkenylene, or alkynylene; the alkylene group, alkenylene group, and alkynylene group are optionally substituted. In some embodiments, L ¹ is a single bond. In another embodiment, L ¹ is alkylene, alkenylene, or alkynylene. In certain embodiments, L ¹ is C _{1 to} C ₆ alkylene, C _{2 to} C ₆ alkenylene, or C _{2 to} C ₆ alkinylene. In particular, L ¹ is a single bond or methylene (-CH ₂ )-.

R ¹ of the present invention, aryl, heteroaryl, arylene, or heteroarylene; aryl, heteroaryl, arylene or heteroarylene group is optionally substituted. In one embodiment, R ¹ is an optionally substituted arylene or heteroarylene.
Specific examples of the arylene of R ¹ include phenylene-1,4-diyl, 3-methyl-phenylene-1,4-diyl, 2,4-methyl-phenylene-1,4-diyl, and 3-methoxy-phenylene-. 1,4-Diyl, 2-fluoro-phenylene-1,4-diyl, 3-fluoro-phenylene-1,4-diyl, phenylene-1,3-diyl, 4-methyl-phenylene-1,3-diyl, Includes 4-methoxy-phenylene-1,3-diyl, 5-methyl-phenylene-1,3-diyl, and naphthalene-1,4-diyl.
Examples of heteroarylene R ¹ is furan-2,5-diyl, thiophene-2,4-diyl, 1,3,4-oxadiazole-2,5-diyl, 1,3,4-thiadiazole -2,5-zyl, 1,3-thiazole-2,4-diyl, 1,3-thiazole-2,5-diyl, pyrazole-3,4-diyl, pyridine-2,3-diyl, pyridine-2 , 4-Zyl, Pyridine-2,5-Zyl, Pyridine-2,5-Zyl, 6-Methyl-Pyridin-2,5-Dyl, Pyridine-2,6-Zyl, Pyrimidin-2,4-Dyl, Pyrimidin Includes −2,5-diyl, quinoline-2,3-diyl, pyridazine-diyl, triazine-diyl and the like.

In the present invention, L ² is a single bond, carbonyl, alkylene, alkenylene, or alkynylene; the alkylene group, alkenylene group, and alkynylene group are optionally substituted. In certain embodiments, L ² is a single bond. In some embodiments, L ² is something other than a single bond. In another particular embodiment, L ² is a carbonyl. In certain embodiments, L ² is C _{1 to} C ₆ alkylene, C _{2 to} C ₆ alkenylene, or C _{2 to} C ₆ alkinylene. In some preferred embodiments, L ² is a single bond, or carbonyl (-C (= O)-).

^{R 2} of the present invention is hydroxyl, alkoxy, aryloxy, or heteroaryloxy, alkoxycarbonylamino, aryloxycarbonylamino, heteroaryloxycarbonylamino, or alkylaminocarbonylamino, arylaminocarbonylamino, heteroarylaminocarbonylamino. , Or NR ⁵ R ⁶ , where each R ⁵ and R ⁶ are independently selected from H, alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, or R ⁵ and R ⁶ are. , They may be combined with the bonded nitrogen atom to form a substituted or unsubstituted heterocycle. Regarding R ² , alkoxy, aryloxy, heteroaryloxy, alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, alkoxycarbonylamino, aryloxycarbonylamino, heteroaryloxycarbonylamino, alkylaminocarbonylamino, arylaminocarbonyl Amino and heteroarylaminocarbonylamino are optionally substituted.

In the present invention, Q ₁ , Q ₂ , Q ₃ and Q ₄ are independently H, hydroxyl, halo, amino, nitro, thiol, carboxyl, cyano, azido, alkyl, alkenyl, alkynyl, cycloalkyl, respectively. Cycloalkenyl, arylalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, heteroaryloxy, sulfanyl, alkylamino, dialkylamino, arylamino, heteroarylamino, acyl, acylamino, aminocarbonyl, alkoxycarbonyl, aryl Consists of a group consisting of oxycarbonyl, heteroaryloxycarbonyl, substituted sulfo, substituted sulfonyl, substituted sulfinyl, aminosulfonyl, sulfonylamino, aminocarbonylamino, aminocarbonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, and heteroaryloxycarbonylamino. Be selected. For each of Q ₁ , Q ₂ , Q ₃ , and Q ₄ , group alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, arylalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, heteroaryloxy, Sulfanyl, alkylamino, dialkylamino, arylamino, heteroarylamino, acyl, acylamino, aminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aminosulfonyl, sulfonylamino, aminocarbonylamino, aminocarbonyloxy, alkoxycarbonyl Aminos, aryloxycarbonylaminos, and heteroaryloxycarbonylaminos are optionally substituted. In some embodiments, Q ₁ , Q ₂ , Q ₃ and Q ₄ are independently H, hydroxyl, halo, amino, nitro, thiol, carboxyl, cyano, azide, C _1- C ₆ alkyl. , C _{2 to} C ₆ alkoxy, C _{2 to} C ₆ alkynyl, C _{3 to} C ₇ cycloalkyl, C _{3 to} C ₇ cycloalkyl, C _{3 to} C ₇ cycloalkoxy, aryl-C _{1 to} C ₆ alkyl C ₁ to It is selected from the group consisting of C ₆ alkoxy, C _{1 to} C ₆ alkylamino, and C _{1 to} C _{6 dialkylamino.} In certain embodiments, _{at least two of Q 1} , Q ₂ , Q ₃ and Q ₄ are non-H and are distinct.

In the present invention, each R ^3a is selected from the group consisting of H, halo, cyano, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkoxy, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, and aminocarbonyl. The group alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkoxy, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, and aminocarbonyl are optionally substituted. In some embodiments, R ^3a is H. ^{R 3a} In another embodiment, halo, _cyano, C 1 -C ₆ alkyl, or _C 1 -C ₆ alkoxycarbonyl.

In the present invention, each R ^3b is independently H, hydroxyl, halo, azide, amino, nitro, thiol, cyano, carboxyl, alkyl, alkenyl, alkynyl, arylalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, Selected from the group consisting of heterocycloalkyl. For each of R ^3b , the group alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, arylalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted. In some embodiments, each R ^3b is H. In some particular embodiments, at least one of ^{R 3b is other than H.} In another ^embodiment, at least one of ^{R 3b} is _C 1 -C ₆ alkyl.

The R ^3c of the present invention is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or heterocycloalkyl, except that if R ^3c is H, L ² is a non-single bond or Whether R ² is other than ^{NR 5} R ^{6 or R 3a} is other than H, or _{two of Q 1} , Q 2, Q ₃ and Q ₄ are non-H and are distinct. .. For R ^3c , groups, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl are optionally substituted. In some embodiments, R ^3c is H. In other embodiments, the R ^3c is C _{1 to} C ₆ alkyl, C _{2 to} C ₆ alkenyl, C _{2 to} C ₆ alkynyl, C _{3 to} C ₇ cycloalkyl, or C _{3 to} C ₇ cycloalkenyl.

In the present invention, W is optionally present, and if present, H, hydroxyl, halo, azide, amino, nitro, thiol, cyano, carboxyl, alkyl, alkenyl, alkynyl, arylalkyl, aryl, heteroaryl, cycloalkyl, Cycloalkenyl, heterocycloalkyl, alkoxy, aryloxy, heteroaryloxy, sulfanyl, alkylamino, dialkylamino, arylamino, heteroarylamino, acyl, acylamino, aminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, Selected from the group consisting of substituted sulfos, substituted sulfonyls, substituted sulfinyls, aminosulfonyls, sulfonylaminos, alkylsulfonyls, arylsulfonyls, aminocarbonylaminos, aminocarbonyloxys, alkoxycarbonylaminos, aryloxycarbonylaminos, and heteroaryloxycarbonylaminos. NS. For W, group alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, arylalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, heteroaryloxy, sulfanyl, alkylamino, dialkylamino, arylamino, heteroaryl Amino, acyl, acylamino, aminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aminosulfonyl, sulfonylamino, aminocarbonylamino, aminocarbonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, and heteroaryloxycarbonylamino. Is optionally replaced. In some embodiments, W is halo, preferably chloro. In other specific embodiments, W is a substituted or unsubstituted heteroarylamino.

Pharmaceutically acceptable salts, hydrates, solvates, prodrugs, isotopic variants, tautomers, and stereoisomers of the compounds of formula (I) are also contemplated by the present invention.

Any combination of two or more embodiments described herein is considered to be within the scope of the invention.

The present invention ^{provides a compound of formula (I), wherein L 1} is a single bond, or substituted or unsubstituted alkylene.

The present invention ^{provides a compound of formula (I), wherein L 2} is a single bond, carbonyl, substituted or unsubstituted alkylene.

Also in the present invention, R ² is hydroxyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, or NR ⁵ R ⁶ (where each R ⁵ and R ⁶ are independent. to H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl, or R ⁵ and R ^6, Together they form a substituted or unsubstituted heterocycle with the attached nitrogen atom), the compound of formula (I) is provided. In another preferred embodiment, the invention provides a compound of formula (I) where m is 0, 1, or 2.

The present invention also ^{provides a compound of formula (I), wherein R 3a} is H, halo, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxycarbonyl; each R ^3b is H independently. ..

The present invention also ^{provides a compound of formula (I), wherein R 3c} is H, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl.

The present invention also _{provides a compound of formula (I), wherein Q 1} , Q ₂ , Q ₃ and Q ₄ are H, halo, cyano, or substituted or unsubstituted alkyl, respectively.

Further, the present invention provides a compound of formula (I) ^{, wherein L 2} is a single bond and R ² is NR ⁵ R ^6.

The present invention also provides a compound of formula (I), wherein ^{L 1} is a substituted or unsubstituted alkylene, a substituted or unsubstituted alkenylene, or a substituted or unsubstituted alkynylene and R ^{1 is a substituted or unsubstituted arylene.}

In the present invention, L ¹ is a substituted or unsubstituted alkylene, a substituted or unsubstituted alkenylene, or a substituted or unsubstituted alkynylene, R ¹ is a substituted or unsubstituted arylene; W is a halo, of the formula (I). Provide compounds.

Also in the present invention, the substituted or unsubstituted arylene is substituted or unsubstituted phenylene-1,4-diyl, substituted or unsubstituted phenylene-1,3-diyl, or substituted or unsubstituted naphthalene-1,4-diyl. , The compound of formula (I) is provided.

Further, in the present invention, each R ^3b is H, m is 0, 1, or 2; if m is 0, d is 2, and if m is 1, d is 3 independently. ; Or if m is 2, d is 4, providing a compound of formula (I).
Also in the present invention, L ¹ is −CH ₂ −; R ¹ is a substituted or unsubstituted arylene group, wherein the substituted or unsubstituted arylene group is a substituted or unsubstituted phenylene-1,4-diyl. Provided are compounds of formula (I), substituted or unsubstituted phenylene-1,3-diyl, or substituted or unsubstituted naphthalene-1,4-diyl.

In the present invention, L ¹ is −CH ₂ −; R ¹ is substituted or unsubstituted phenylene-1,4-diyl, or substituted or unsubstituted phenylene-1,3-diyl, and R ^3a is. Provided are compounds of formula (I), which are H, halo, CN, substituted or unsubstituted C _{1 to} C _{6 alkyl, or substituted or unsubstituted alkoxycarbonyl.}

The present invention also provides a compound of formula (I) ^{, where L 1} is a single bond and R ^{1 is a substituted or unsubstituted arylene.}

The present invention also provides a compound of formula (I), wherein W is a substituted or unsubstituted heteroarylamino.

The invention further describes that L ¹ is a single bond; R ¹ is a substituted or unsubstituted arylene; W is a substituted or unsubstituted heteroarylamino, each R ^3b is H; m is 0, 1, Or 2; if m is 0, d is 2; if m is 1, d is 3 independently; or if m is 2, d is 4. The compound of I) is provided.

Also in the present invention, R ¹ is substituted or unsubstituted phenylene-1,4-diyl, substituted or unsubstituted phenylene-1,3-diyl, or substituted or unsubstituted naphthalene-1,4-diyl; R ^3a is , Halo, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxycarbonyl, the compound of formula (I) is provided.
The present invention further ^{provides a compound of formula (I), wherein R 1} is substituted or unsubstituted phenylene-1,4-diyl, or substituted or unsubstituted phenylene-1,3-diyl.

The invention also ^{provides a compound of formula (I), where L 1} is a single bond; R ¹ is a substituted or unsubstituted heteroarylene; W is a substituted or unsubstituted heteroarylamino.

Further, in the present invention, L ¹ is a single bond; R ¹ is a substituted or unsubstituted heteroarylene; W is a substituted or unsubstituted heteroarylamino; each R ^3b is H; m is 0, 1. , Or 2; if m is 0, d is 2; if m is 1, d is 3 independently; or if m is 2, d is 4. The compound of (I) is provided.

In the present invention, R ¹ is a substituted or unsubstituted pyridine diyl, a substituted or unsubstituted pyrimidin diyl, a substituted or unsubstituted pyrazine diyl, a substituted or unsubstituted 1H-pyrazole diyl, an oxazole diyl, or a substituted or unsubstituted isoxazole diyl. ; ^{R 3a,} provides halo, cyano, or substituted or unsubstituted _C 1 -C ₆ alkyl, substituted or unsubstituted alkoxycarbonyl, a compound of formula (I).

The invention further comprises ^{the formula (I), wherein R 1} is substituted or unsubstituted pyridine-2,4-diyl, substituted or unsubstituted pyridine-2,5-diyl, or substituted or unsubstituted pyridine-2,6-diyl. ) Is provided. In a further preferred embodiment, W is a pyrimidine-2-yl-amino, pyrimidine-4-yl-amino, pyrimidine-5-yl-amino, 1H-pyrazole-5-yl-amino, 1H-pyrazole. -4-yl-amino, flo [2,3-d] pyrimidine-2-yl-amino, pyridin-2-yl-amino, pyridin-3-yl-amino, or pyridine-4-yl-amino, The compound of the formula (I) is provided.

Suitable compounds of the present invention include:
2- (4-Chlorobenzylamino) -4- [3- (pyrrolidin-1-yl) azetidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -4- [3- (morpholine-4-yl) azetidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -4- [4- (methylcarbamoyl) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -4- [4- (tert-butylaminocarbonyl) -piperidine-1-yl] -quinoline,
2- (4-Chlorobenzylamino) -4- [4- (pyrrolidin-1-carbonyl) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -4- [4- (4-methylpiperazine-1-carbonyl) -piperidine-1-yl] -quinoline,
(2S) 2- (4-chlorobenzylamino) -4- [2- (hydroxymethyl) pyrrolidine-1-yl] quinoline,
(2S) 2- (4-chlorobenzylamino) -4- [2- (methoxymethyl) pyrrolidine-1-yl] quinoline,
(2R) -2- (4-chlorobenzylamino) -4- [2- (hydroxymethyl) -pyrrolidin-1-yl] -quinoline,
2- (4-Chlorobenzylamino) -4- (4-hydroxypiperidine-1-yl) quinoline,
2- (4-Chlorobenzylamino) -4- [4- (iso-propoxy) -piperidine-1-yl] -quinoline,
2- (4-Chlorobenzylamino) -4- (4-phenoxypiperidine-1-yl) -quinoline,
2- (4-Chlorobenzylamino) -4- [4- (m-tolyloxy) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -4- [4- (pyridin-4-yloxy) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -4- [4- (pyrazine-2-yloxy) piperidine-1-yl] quinoline,
(3R) 2- (4-chlorobenzylamino) -4- (3-hydroxypyrrolidin-1-yl) quinoline,
(3R) 2- (4-chlorobenzylamino) -4- [3- (phenoxy) pyrrolidine-1-yl] quinoline,
(3R) 2- (4-chlorobenzylamino) -4- [3- (pyridin-2-yloxy) pyrrolidine-1-yl] quinoline,
(3S) 2- (4-chlorobenzylamino) -4- (3-hydroxypyrrolidin-1-yl) -quinoline,
(3S) 2- (4-chlorobenzylamino) -4- [3- (pyridin-2-yloxy) pyrrolidine-1-yl] quinoline,
2- (N-4-chlorobenzyl-N-methylamino) -4- [4- (tert-butylamino) -piperidine-1-yl] -quinoline,
2- (N-4-chlorobenzyl-N-ethylamino) -4- [4- (tert-butylamino) -piperidine-1-yl] -quinoline,
2- (N-4-chlorobenzyl-N-isopropylamino) -4- [4- (tert-butylamino) -piperidine-1-yl] -quinoline,
2- (N-4-chlorobenzyl-N-isobutylamino) -4- [4- (tert-butylamino) -piperidine-1-yl] -quinoline,
2- (4-Chlorobenzylamino) -3-fluoro-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-methyl-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
Methyl 4- (4- (tert-butylamino) piperidine-1-yl) -2- (4-chlorobenzylamino) quinoline-3-carboxylate,
2- (4-Chlorobenzylamino) -4- [4- (tert-butylamino) piperidine-1-yl] -7-methyl-8-fluoroquinoline,
2- (4-Chlorobenzylamino) -4- [4- (tert-butylamino) piperidine-1-yl] -6-methyl-8-fluoroquinoline,
2- (4-Chlorobenzylamino) -4- [4- (tert-butylamino) piperidine-1-yl] -7-fluoro-8-methylquinoline,
2- (4-Chlorobenzylamino) -4- [4- (tert-butylamino) piperidine-1-yl] -6-fluoro-8-methylquinoline,
2- [4- (4-Methylpyrimidine-2-ylamino) phenylamino] -3-methyl-4- (4-tert-butylaminopiperidine-1-yl) quinoline,
2- [3- (4-Trifluoromethylpyrimidine-2-ylamino) phenylamino] -3-methyl-4- (4-tert-butylaminopiperidine-1-yl) quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- [4- (4- (Pyridine-3-yl) pyrimidin-2-ylamino) -3-methylbenzylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline,
2- (3-Methyl-4- (4-methylpyrimidine-2-ylamino) phenylamino) -3-cyano-4- (4- (tert-butylamino) piperidine-1-yl) -quinoline,
2- [4- (4,6-dimethyl-2-pyrimidineamino) -3-methyl-phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline,
2- [4- (4-Methyl-6-Methoxypyrimidine-2-ylamino) -3-methylphenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline,
2- [3-Methyl-4- (4,6-dimethylflo [2,3-d] pyrimidin-2-ylamino) Phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) ) Quinoline,
2- {3-Methyl-4- [2- (pyridin-3-yl) pyrimidin-4-ylamino] phenylamino} -3-cyano-4- (4-tert-butylaminopiperidin-1-yl) quinoline,
2- {3-Methyl-4- [2- (pyridin-3-yl) -5-cyanopyrimidine-4-ylamino] phenylamino} -3-cyano-4- (4-tert-butylaminopiperidine-1-) Il) quinoline,
2- [4- (4-Methylpyrimidine-2-ylamino) phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline,
2- [3-Methyl-4- (4-trifluoromethylpyrimidine-2-ylamino) phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline,
2- [3- (4-Trifluoromethyl-2-pyrimidineamino) -4-methyl-phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline,
2- [3- (4-Trifluoromethylpyrimidine-2-ylamino) phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline,
2- (4- (4- (Pyridine-3-yl) pyrimidin-2-ylamino) -3-methylphenylamino] -3-cyano-4- (4-tert-butylaminopiperidin-1-yl) quinoline,
2- [3- (4-Trifluoromethylpyrimidine-2-ylamino) phenylamino] -3-fluoro-4- (4-tert-butylaminopiperidine-1-yl) quinoline,
2- (4-Fluorobenzylamino) -3-fluoro-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (4-Fluorobenzylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] -8-methylquinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] -7-methylquinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] -6-methylquinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- (3-aminopiperidin-1-yl) quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (methylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (isopropylamino) piperidine-1-yl] quinoline,
{[(Tetrahydro-2H-pyra-4-yl) methyl] amino} -3-fluoro-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (cyclopentylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (4-methylpiperazine-1-yl) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4-{3-[(1-methylpiperidine-4-yl) amino] piperidine-1-yl} quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (pyrrolidin-1-yl) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (morpholino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (4-methylpiperazine-1-yl) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (dimethylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (diethylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- (4-aminopiperidine-1-yl) quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (methylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (isopropylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4-{4-[(tert-butyloxycarbonyl) amino] piperidine-1-yl} quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (cyclopentylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4-{4-[(tetrahydro-2H-pyran-4-yl) amino] piperidine-1-yl} quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4-{4-[(1-methylpiperidine-4-yl) amino] piperidine-1-yl} quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (pyrrolidin-1-yl) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (morpholino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (4-methylpiperazine-1-yl) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (dimethylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (diethylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3-aminopyrrolidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (methylamino) pyrrolidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (cyclopentylamino) pyrrolidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4-{3-[(tetrahydro-2H-pyran-4-yl) amino] pyrrolidine-1-yl} quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (pyrrolidin-1-yl) pyrrolidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- (3-morpholinopyrrolidine-1-yl) quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (4-methylpiperazin-1-yl) pyrrolidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (dimethylamino) pyrrolidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (diethylamino) pyrrolidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- (3-phenoxypiperidine-1-yl) quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (4-methoxyphenoxy) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (4-methylphenoxy) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (4-fluorophenoxy) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (3-fluorophenoxy) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4-{3-[(3-methylpyrazine-2-yl) oxy] piperidine-1-yl} quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- (4-phenoxypiperidine-1-yl) quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (4-methoxyphenoxy) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (p-tolyloxy) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (4-chlorophenoxy) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (4-fluorophenoxy) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (3-fluorophenoxy) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4-{4-[(pyridin-4-yl) oxy] piperidine-1-yl} quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4-{4-[(5-methylisoxazole-3-yl) oxy] piperidine-1-yl} quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4-{4-[(3-methylpyrazine-2-yl) oxy] piperidine-1-yl} quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- (3-phenoxypyrrolidine-1-yl) quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (4-methylphenoxy) pyrrolidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (4-methoxyphenoxy) pyrrolidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (4-chlorophenoxy) pyrrolidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (4-fluorophenoxy) pyrrolidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (3-fluorophenoxy) pyrrolidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4-{3-[(3-methylpyrazine-2-yl) oxy] pyrrolidine-1-yl} quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4-{3-[(pyridin-4-yl) oxy] pyrrolidine-1-yl} quinoline,
2- (Phenylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (4-Methylphenylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (3-Methyl-4-fluorophenylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (4-Methoxyphenylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (2-Trifluoromethylphenylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (3-Trifluoromethylphenylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (4-Chlorophenylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (4-Fluorophenylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (3-Fluorophenylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (3,4-difluorophenylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- [4- (trifluoromethyloxy) phenylamino] -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2-[(1-Methyl-1H-pyrazole-4-yl) amino] -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2-[(1-Methyl-1H-1,2,4-triazole-5-yl) amino] -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2-[(1,3-dimethyl-1H-1,2,4-triazole-5-yl) amino] -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- {4- [(4,6-dimethylpyrimidine-2-yl) amino] phenylamino} -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (Pyridine-2-ylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (Pyrimidine-2-ylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (Pyrimidine-4-ylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (Pyrazine-2-ylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (Benzylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (4-Methylbenzylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (4-Methoxybenzylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- [4- (Trifluoromethyl) benzylamino] -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- [2- (Trifluoromethyl) benzylamino] -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2-[(Benzo [d] [1,3] dioxol-5-ylmethyl) amino] -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2-[(Fran-2-ylmethyl) amino] -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2-[(Pyridine-3-ylmethyl) amino] -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2-[(Pyridine-4-ylmethyl) amino] -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2-[(Pyridine-2-ylmethyl) amino] -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline.

Or a hydrate thereof, a solvate, or a prodrug, or an isotope variant thereof, a tautomer, or a stereoisomer thereof.

［ここで
−Ｌ^２は、単結合、カルボニル、置換もしくは非置換アルキレン、置換もしくは非置換アルケニレン、又は置換もしくは非置換アルキニレンであり；
−Ｒ^２は、ヒドロキシル、置換もしくは非置換アルコキシ、置換もしくは非置換アリールオキシ、置換もしくは非置換ヘテロアリールオキシ、置換もしくは非置換アルコキシカルボニルアミノ、置換もしくは非置換アリールオキシカルボニルアミノ、置換もしくは非置換ヘテロアリールオキシカルボニルアミノ、置換もしくは非置換アルキルアミノカルボニルアミノ、置換もしくは非置換アリールアミノカルボニルアミノ、置換もしくは非置換ヘテロアリールアミノカルボニルアミノ、又はＮＲ^５Ｒ^６（ここで、各Ｒ^５及びＲ^６は、独立してＨ、置換もしくは非置換アルキル、置換もしくは非置換シクロアルキル、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリール、又は置換もしくは非置換ヘテロシクロアルキルであるか、又はＲ^５及びＲ^６は、それらが結合している窒素原子と一緒になって、置換もしくは非置換複素環を形成する）であり；
−Ｒ^３ａは、Ｈ、ハロ、シアノ、置換もしくは非置換アルキル、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリール、置換もしくは非置換シクロアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アルコキシ、置換もしくは非置換アルコキシカルボニル、置換もしくは非置換アリールオキシカルボニル、置換もしくは非置換ヘテロアリールオキシカルボニル、又は置換もしくは非置換アミノカルボニルであり；
−各Ｒ^３ｂは、独立してＨ、ヒドロキシル、ハロ、アジド、アミノ、ニトロ、チオール、シアノ、カルボキシル、置換もしくは非置換アルキル、置換もしくは非置換アルケニル、置換もしくは非置換アルキニル、置換もしくは非置換アリールアルキル、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリール、置換もしくは非置換シクロアルキル、置換もしくは非置換シクロアルケニル、又は置換もしくは非置換ヘテロシクロアルキルであり；
−Ｒ^３ｃは、Ｈ、置換もしくは非置換アルキル、置換もしくは非置換アルケニル、置換もしくは非置換アルキニル、置換もしくは非置換シクロアルキル、置換もしくは非置換シクロアルケニル、又は置換もしくは非置換ヘテロシクロアルキルであるが、ただし、Ｒ^３ｃがＨである場合、Ｌ^２は単結合以外であるか、又はＲ^２はＮＲ^５Ｒ^６以外であるか、又はＲ^３ａはＨ以外であり；
−ｍは、０、１、２、３、又は４であり；
ｍが０である場合、ｄは独立して０、１、又は２であり；ｍが１である場合、ｄは独立して０、１、２、又は３であり；ｍが２である場合、ｄは独立して０、１、２、３、又は４であり；ｍが３である場合、ｄは独立して０、１、２、３、４、又は５であり、又はｍが４である場合、ｄは独立して０、１、２、３、４、５、又は６である］の構造、 A suitable compound of the present invention is the following formula (II) :.

[Here-L ² is a single bond, carbonyl, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted alkynylene;
-R ² is hydroxyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted alkoxycarbonylamino, substituted or unsubstituted aryloxycarbonylamino, substituted or unsubstituted hetero. Aryloxycarbonylamino, substituted or unsubstituted alkylaminocarbonylamino, substituted or unsubstituted arylaminocarbonylamino, substituted or unsubstituted heteroarylaminocarbonylamino, or NR ⁵ R ⁶ (where R ⁵ and R ⁶ are respectively. Independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl, or R ⁵ and R ⁶ are , Together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocycle);
-R ^3a is H, halo, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkoxy. , Substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, or substituted or unsubstituted aminocarbonyl;
^-Each R 3b is independently H, hydroxyl, halo, azide, amino, nitro, thiol, cyano, carboxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl. Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocycloalkyl;
-R ^3c is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocycloalkyl. However, if R ^3c is H, then L ² is something other than a single bond, or R ² is something other than ^{NR 5} R ^{6 , or R 3a} is something other than H;
−M is 0, 1, 2, 3, or 4;
If m is 0, d is independently 0, 1, or 2; if m is 1, d is independently 0, 1, 2, or 3; if m is 2. , D independently are 0, 1, 2, 3, or 4; if m is 3, then d is independently 0, 1, 2, 3, 4, or 5, or m is 4 If d is independently 0, 1, 2, 3, 4, 5, or 6] structure,

Alternatively, it has a pharmaceutically acceptable salt, hydrate, solvate, or prodrug, or an isotope variant, tautomer, or stereoisomer thereof.

The present invention ^{provides specific compounds of formula (II), wherein R 3c} is H, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl.

The present invention provides specific compounds of formula (II), where ^{each R 3b is H independently.}

The present invention also ^{provides specific compounds of formula (II), wherein R 3a} is H, halo, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxycarbonyl.
The present invention also ^{provides a particular compound of formula (II), wherein L 2} is a single bond, carbonyl, substituted or unsubstituted alkylene.

The present invention also provides a particular compound of formula (II), where m is 0, 1, or 2.

Representative compounds of formula (I) of the present invention include, but are not limited to, compounds of formula (II) shown in Table 1 below:

［ここで：
−Ｑ_１、Ｑ_２、Ｑ_３、及びＱ_４は、それぞれ独立して、Ｈ、ヒドロキシル、ハロ、アミノ、ニトロ、チオール、カルボキシル、シアノ、アジド、置換もしくは非置換アルキル、置換もしくは非置換アルケニル、置換もしくは非置換アルキニル、置換もしくは非置換シクロアルキル、置換もしくは非置換シクロアルケニル、置換もしくは非置換アリールアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリール、置換もしくは非置換アルコキシ、置換もしくは非置換アリールオキシ、置換もしくは非置換ヘテロアリールオキシ、置換もしくは非置換スルファニル、置換もしくは非置換アルキルアミノ、置換もしくは非置換ジアルキルアミノ、置換もしくは非置換アリールアミノ、置換もしくは非置換ヘテロアリールアミノ、置換もしくは非置換アシル、置換もしくは非置換アシルアミノ、置換もしくは非置換アミノカルボニル、置換もしくは非置換アルコキシカルボニル、置換もしくは非置換アリールオキシカルボニル、置換もしくは非置換ヘテロアリールオキシカルボニル、置換スルホ、置換スルホニル、置換スルフィニル、置換もしくは非置換アミノスルホニル、置換もしくは非置換スルホニルアミノ、置換もしくは非置換アミノカルボニルアミノ、置換もしくは非置換アミノカルボニルオキシ、置換もしくは非置換アルコキシカルボニルアミノ、置換もしくは非置換アリールオキシカルボニルアミノ、又は置換もしくは非置換ヘテロアリールオキシカルボニルアミノであり；Ｑ_１、Ｑ_２、Ｑ_３、及びＱ_４の少なくとも２個はＨ以外であり、かつ別個である］。
好ましくは、Ｑ_１、Ｑ_２、Ｑ_３、及びＱ_４は、それぞれ独立してＨ、シアノ、メチル、又はハロである。 The present invention also provides, in a preferred embodiment, a compound of formula (III) having the following structure:

[here:
-Q ₁ , Q ₂ , Q ₃ and Q ₄ are independently H, hydroxyl, halo, amino, nitro, thiol, carboxyl, cyano, azide, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, respectively. Substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or Unsubstituted alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted sulfanyl, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted arylamino, substituted or unsubstituted. Heteroarylamino, substituted or unsubstituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted sulfo, Substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted sulfonylamino, substituted or unsubstituted aminocarbonylamino, substituted or unsubstituted aminocarbonyloxy, substituted or unsubstituted alkoxycarbonylamino, substituted or unsubstituted aryloxy carbonyl, amino, or substituted or unsubstituted heteroaryl _{aryloxycarbonylamino;} Q _1, at least two Q 2, _{Q 3,} and _{Q 4} is other than H, and a separate.
Preferably, Q ₁ , Q ₂ , Q ₃ and Q ₄ are independently H, cyano, methyl, or halo, respectively.

Representative compounds of the present invention include, but are not limited to, the compounds shown in Table 2 below and the compounds of the following formula (III).

［ここで、Ｑ_１、Ｑ_２、Ｑ_３、及びＱ_４は、式Ｉで定義されたものである。好ましくはＱ_１、Ｑ_２、Ｑ_３、及びＱ_４は、それぞれ独立して、Ｈ、ハロ、置換もしくは非置換アルキル、置換もしくは非置換アルコキシである］。 The present invention also provides, in a preferred embodiment, a compound of formula (III') having the following structure:

[Here, Q ₁ , Q ₂ , Q ₃ and Q ₄ are defined by the formula I. Preferably Q ₁ , Q ₂ , Q ₃ and Q ₄ are H, halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, respectively].

Representative compounds of the present invention include, but are not limited to, the compounds shown in Table 2'below and the formula (III') below.

［ここで
−Ｒ^３ａは、ハロ、シアノ、置換もしくは非置換アルキル、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリール、置換もしくは非置換シクロアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アルコキシ、置換もしくは非置換アルコキシカルボニル、置換もしくは非置換アリールオキシカルボニル、置換もしくは非置換ヘテロアリールオキシカルボニル、又は置換もしくは非置換アミノカルボニルであり；
−Ｌ^１は、単結合、又は置換もしくは非置換アルキレン、置換もしくは非置換アルケニレン、又は置換もしくは非置換アルキニレンであり；
−Ｒ^１は、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリール、置換もしくは非置換アリーレン、又は置換もしくは非置換ヘテロアリーレンであり；そして
−Ｗは、場合により存在し、存在する場合は、Ｈ，ヒドロキシル、ハロ、アジド、アミノ、ニトロ、チオール、シアノ、カルボキシル、置換もしくは非置換アルキル、置換もしくは非置換アルケニル、置換もしくは非置換アルキニル、置換もしくは非置換アリールアルキル、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリール、置換もしくは非置換シクロアルキル、置換もしくは非置換シクロアルケニル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アルコキシ、置換もしくは非置換アリールオキシ、置換もしくは非置換ヘテロアリールオキシ、置換もしくは非置換スルファニル、置換もしくは非置換アルキルアミノ、置換もしくは非置換ジアルキルアミノ、置換もしくは非置換アリールアミノ、置換もしくは非置換ヘテロアリールアミノ、置換もしくは非置換アシル、置換もしくは非置換アシルアミノ、置換もしくは非置換アミノカルボニル、置換もしくは非置換アルコキシカルボニル、置換もしくは非置換アリールオキシカーボニル、置換もしくは非置換ヘテロアリールオキシカルボニル、置換スルホ、置換スルホニル、置換スルフィニル、置換もしくは非置換アミノスルホニル、置換もしくは非置換スルホニルアミノ、置換もしくは非置換アルキルスルホニル、置換もしくは非置換アリールスルホニル、置換もしくは非置換アミノカルボニルアミノ、置換もしくは非置換アミノカルボニルオキシ、置換もしくは非置換アルコキシカルボニルアミノ、置換もしくは非置換アリールオキシカルボニルアミノ、又は置換もしくは非置換ヘテロアリールオキシカルボニルアミノである］。 The present invention also provides a specific compound of formula (IV) having the following structure:

[Here, -R ^3a is halo, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted. Alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, or substituted or unsubstituted aminocarbonyl;
-L ¹ is a single bond, or substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted alkynylene;
-R ¹ is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; and -W is optionally present and H, if present. , Hydroxyl, halo, azide, amino, nitro, thiol, cyano, carboxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or Unsubstituted heteroaryl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or Unsubstituted sulfanyl, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted arylamino, substituted or unsubstituted heteroarylamino, substituted or unsubstituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted amino Carbonyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted sulfo, substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted sulfonylamino, substituted Alternatively, unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted aminocarbonylamino, substituted or unsubstituted aminocarbonyloxy, substituted or unsubstituted alkoxycarbonylamino, substituted or unsubstituted aryloxycarbonylamino, or substituted or non-substituted. Substituted heteroaryloxycarbonylamino].

Further, the present invention ^{provides a specific compound according to formula (IV), wherein R 3a} is a halo, cyano, or substituted or unsubstituted alkoxycarbonyl.
The present invention is also, L ¹ is a single bond, or a substituted or unsubstituted alkylene, to provide certain compounds of formula (IV).

The present invention ^{provides a further specific compound of formula (IV), wherein R 1} is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.
The present invention also provides another particular compound of formula (IV), wherein W is a substituted or unsubstituted arylamino, or a substituted or unsubstituted heteroarylamino.

The representative compound of the formula (IV) is not particularly limited, but includes the compounds shown in Table 3 below.

All stereoisomers of the compound of formula (I) (eg, those that may be present due to asymmetric carbons on various substituents), enantiomers, and diastereoisomers are in the mixture or pure. Alternatively, the compounds of the invention, which are considered to be within the scope of the invention in substantially pure formation, can have an asymmetric center at any carbon atom. As a result, they can be present in the form of racemates, pure mirror isomers and / or diastereoisomers, or in the form of mixtures of these mirror image isomers and / or diastereoisomers. The mixture can have the desired mixing ratio of the stereoisomers. Thus, for example, a compound of the invention having one or more chirality centers and present as a racemic compound or a mixture of diastereoisomers can be optically pure isomers, i.e. mirror isomers, by methods known per se. It can be fractionated into a body or a diastereoisomer. The chiral center of the invention may have an S or R configuration as defined by IUPAC 1974 Recommendations. Separation of the compounds of the invention, which may be present in racemic or diastereomeric mixtures, is performed by column separation in a chiral or non-chiral phase, fractional crystallization, or optionally recrystallization from an optically active solvent, or optically active. It can be carried out by the use of an acid or base, or by derivatization with an optically active reagent such as, for example, an optically active alcohol, and subsequent desorption of the group. In some examples, the compounds of the invention can have one or more double bonds in which each double bond is present in an E (trans) or Z (cis) configuration, or a combination thereof. Techniques for reversing or leaving a specific stereocenter unaltered, and for splitting a mixture of stereoisomers, are, for example, Furniss et al. (E.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5th Edition, Longman Scientific and Found in Technical Ltd., Essex, 1991, 809-816; and Heller, Acc. Chem. Res. 1990, 23, 128.

If possible, the compounds of the invention may be in the form of tautomers, eg keto-enol tautomers.

The compounds of formula (I) (or (II), (III), (III'), or (IV)) may be provided in any form suitable for their intended use in treatment. Suitable forms include pharmaceutically acceptable salts, hydrates, solvates, polymorphs, prodrugs, and isotopic variants within the scope of the invention.

As used herein, the term "salt" refers to an acidic and / or basic salt formed of an inorganic and / or organic acid and base. Further, the compound of the formula (I) contains both a basic moiety such as, but not limited to, pyridinyl, imidazolyl, or amine, and an acidic moiety such as, but not particularly limited, a carboxylic acid. If zwitterion is formed, it is included in the term "salt" as used herein. Pharmaceutically acceptable (ie, non-toxic, physiologically acceptable) salts are preferred, but other salts are also useful, for example, in isolation or purification steps that may be used during preparation. The salt of the compound of the formula (I) is prepared by reacting, for example, the compound of the formula (I) with a certain amount, for example, an equivalent amount of an acid or a base in a medium or an aqueous medium in which the salt precipitates, and then freeze-drying. Can be formed by
A list of suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences", 22nd Edition, Allen Loyd V. Jr., (2012); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" 2nd Edition, Stahl and Found in Wermuth (Wiley-VCH, Weinheim, Germany, 2011).

The compound of formula (I) containing, but not limited to, an amine or a basic moiety such as a pyridyl or pyrimidinyl ring can form salts with various organic and inorganic acids. Examples of acid addition salts include acetates (eg, acetic acid or trihaloacetic acid, such as those formed with trifluoroacetic acid), adipates, alginates, ascorbates, asparagitates, benzoates, benzenesulfons. Acids, bicarbonates, borates, butyrate, citrates, sulphates, sulphates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, Glucoheptanate, glycerophosphate, hemisulfate, heptaneate, hexanate, hydrochloride, hydrobromide, hydroiodide, hydroxyetan sulfonate (eg 2-hydroxyethan sulfonate) ), Lactate, maleate, methanesulfonate, naphthalenesulfonate (eg 2-naphthalenesulfonate), nicotinate, nitrate, sulphate, pectinate, persulfate, phenylpropionate (Eg 3-phenylpropionate), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (eg formed with sulfuric acid), sulfonates (eg, those formed with sulfuric acid) As referred to herein), tartrate, thiocyanate, toluenesulfonate, such as tosilate, undecanoate and the like.

Compounds of formula (I), including but not limited to acidic moieties such as carboxylic acids, can form salts with a variety of organic and inorganic bases. Exemplary basic salts include ammonium salts; alkali metal salts such as sodium salts, lithium salts, and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; salts with organic bases (eg organic amines). , For example benzatin, dicyclohexylamine, hydrabamine (formed with N, N-bis (dehydroaviethyl) ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glycamide, t-butylamine, and arginine, lysine. Contains salts with amino acids such as. Basic nitrogen-containing groups include lower alkyl halides (eg, chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl), dialkyl sulfates (eg, dimethyl, diethyl, dibutyl, and diamil sulfates), long chains. It is quaternized using halides (eg, decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (eg, benzyl bromide and phenethyl bromide), and the like.

The term "hydrate" means a compound of the invention described herein further comprising a stoichiometric or non-stoichiometric amount of water bound by a non-covalently intermolecular force. The hydrate includes, but is not limited to, hemihydrate, monohydrate, dihydrate, trihydrate and the like. Hydrate of the compounds of the invention and their pharmaceutically acceptable salts can be selected by preparing these compounds or their pharmaceutically acceptable salts by contacting them with water under appropriate conditions. The hydrate can be produced.

The term "solvate" means a compound of the invention described herein further comprising a stoichiometric or non-stoichiometric amount of solvent bonded by a non-covalently intermolecular force. In some embodiments, the solvate can be formed during a crystallization process using a solvent such as water, ethanol. Non-limiting examples of solvates include hydrates that can be formed when the solvent is water and alcoholates which can be formed when the solvent is an alcohol. Solvasates of the compounds described herein can be conveniently prepared or formed during the process described herein. As just one example, the hydrates of the compounds described herein are not particularly limited, but recrystallize from an aqueous / organic solvent mixture using an organic solvent containing dioxane, tetrahydrofuran, or methanol. Therefore, it can be conveniently prepared. In addition, the compounds provided herein can exist in unsolvated and solvated forms. Generally, the solvated form is considered to be equivalent to the non-solvated form for the purposes of the compounds provided herein and their uses.

The term "prodrug" means a derivative of a compound that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide the compounds of the invention. Prodrugs can be active under biological conditions in such reactions or have activity in their unreacted form. In addition, prodrugs can be converted to the compounds of this application by chemical or biochemical methods in an in vitro environment. For example, a prodrug can be slowly converted to a compound of the present application when placed in a transdermal patch reservoir using a suitable enzyme or chemical reagent. Prodrugs can be formed using means commonly known in the art and thus can take essentially any form recognized by those of skill in the art. The moieties modified to form a prodrug include reactive functional groups such as hydroxyl, carboxyl, amino, and thiol. Specific examples of hydroxyl modifying groups include acetyl, propionyl, isobutyryl, pivaloyl, benzoyl, 4-methylbenzoyl, dimethylcarbamoyl, alkoxycarbonyl (eg, ethoxycarbonyl), monoesters formed with dicarboxylic acids (eg, succinyl), phosphorus. Includes esters, sulfates, sulfonates, sulfonyls, sulfinyl and the like. Specific examples of the modifying group of carboxymethyl include ethyl, pivaloyloxymethyl, 1- (acetyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1- (cyclohexyloxycarbonyloxy) ethyl, carboxymethyl and methyl. (5-Methyl-2-oxo-1,3-dioxol-4-yl), phenyl, o-tolyl and the like are included.
Specific examples of amino modifying groups include hexylcarbamoyl, 3-methylthio-1- (acetylamino) propylcarbonyl, 1-sulfo-1- (3-ethoxy-4-hydroxyphenyl) -methyl, methyl (5-methyl). -2-oxo-1,3-dioxol-4-yl) and the like are included. Various forms of prodrugs are known in the art, eg (i) Wermuth CG et al., Chapter 31: 671-696, The Practice of Medicinal Chemistry, Academic Press 1996; (ii) Bundgaard H, Design of Prodrugs, Elsevier 1985; and (iii) Bundgaard H, Chapter 5: 131-191, A Textbook of Drug Design and Development, Harwood Academic Publishers 1991. The literature is incorporated herein by reference.
Prodrugs are often useful because they can be easier to administer than the parent drug in some circumstances. They may be biologically available, for example by oral administration, but not the parent drug. Particularly preferred derivatives or prodrugs are the bioavailability of the compounds of the invention when such compounds are administered to an individual (eg, by allowing the orally administered compound to be more easily absorbed into the blood). Or enhance the delivery of the parent compound to a biological compartment (eg, brain or lymphatic system).

As used herein, "isotope variant" refers to a compound of the present disclosure, including the pharmaceutical salts, hydrates, solvates, and prodrugs described herein, respectively. In, one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine (eg, ² H, ³ H, ¹³ C, ¹⁴ C, respectively). ¹⁵ N, ¹⁸⁰ , ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ C1) are included. Isotopic variants of the disclosed compounds may be useful in tissue distribution assays for drugs and / or substrates. Tritylated ( ³ H) and carbon-14 ( ¹⁴ C) labeled compounds are particularly preferred due to their ease of preparation and detection. Further, substitution with heavier isotopes such as deuterium ^{(2 H)} may afford greater certain therapeutic advantages resulting from metabolic stability, can result in a reduction in the increase or dosage requirements for example in vivo half-life, thus It may be preferable in some situations. Isotope variants of the compounds of the invention, including pharmaceutical salts, esters, solvates, hydrates, and prodrugs, can be prepared by any means known in the art. Furthermore, substitution of the normal rich hydrogen ^{(1 H)} with heavier isotopes such as deuterium, for example, improved absorption, distribution, giving metabolism, and / or excretion (ADME) therapeutic advantages resulting from the characteristic And can produce drugs with improved efficacy, safety, and / or tolerability. It is also possible to make a profit by replacing ^{the normally abundant 12} C with ^{13 C.} See International Publication No. 2007/005643, International Publication No. WO2007 / 005644, International Publication No. 2007/016361, and International Publication No. 2007/016431.

In some examples, the compounds of the invention or pharmaceutically acceptable salts or prodrugs thereof may be present in various polymorphic forms, and certain modifications may be more metastable. .. All of these polymorphic forms should be considered to belong to the present invention. As used herein, the term "polymorph" means the solid crystalline form of the compounds of the invention described herein. Different polymorphs of the same compound may exhibit different physical, chemical, and / or spectroscopic properties. The different physical properties are not particularly limited, but are stable (eg, heat or light), compressibility, and density (important in formulation and product manufacture), and dissolution rate (which is biological). May affect usability). Differences in stability can be chemical reactivity (eg, differential oxidation such that the dosage form changes color more rapidly if it consists of one polymorph rather than another), or mechanical properties (eg, thermodynamics). The preferred polymorphs are converted to thermodynamically more stable polymorphs and the tablets crumble during storage), or both (eg, one polymorphic tablet is more fragile at high humidity) resulting from changes. obtain. The different physical properties of polymorphs can affect their processing. For example, one polymorph may be easier to form a solvate or more difficult to filter or wash than the other, for example because of the shape, size, or particle size distribution of its particles.

In addition, it is known that chemicals are converted into metabolites in the body, which, where appropriate, can, in some situations, elicit the desired biological effect, even in more prominent forms. .. Any biologically active compound converted in vivo by metabolism from any of the compounds of the invention is a metabolite within the scope and spirit of the invention. As used herein, the term "metabolite" refers to a derivative of a compound that is formed when the compound is metabolized. As used herein, the term "active metabolite" refers to a biologically active derivative of a compound that is formed when the compound is metabolized. As used herein, the term "metabolized" refers to the entire process by which an organism changes a particular substance, including, but not limited to, hydrolysis reactions and enzyme-catalyzed reactions. Point to. That is, the enzyme can cause a structural change specific to the compound. For example, cytochrome P450 catalyzes various redox reactions, whereas uridine diphosphate glucuronide transferase is an active glucuronic acid molecule to aromatic alcohols, fatty alcohols, carboxylic acids, amines, and free sulfhydryl groups. Catalyze the transition. Further information on metabolism is available from The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996).

III. General Synthetic Methods for Preparing Compounds of the Invention The present invention further provides general methods for preparing compounds of formula (I) as defined above.

The compound of formula (I) of the present invention can be prepared using various organic chemical methods including those known to those skilled in the art.

In some embodiments, the synthesis of the compound of formula (I) of the invention can be carried out according to a general synthetic procedure comprising the following steps (see also Scheme I).

（ここで、Ｘ、Ｘ’は独立してハロであり、Ｒ^３ａ、Ｑ_１、Ｑ_２、Ｑ_３、及びＱ_４は、一般式（Ｉ）で定義した通りである）を有する式（Ｉ−ａ）の化合物に、
下記構造：

（ここで、Ｌ^１、Ｒ^１、Ｒ^３ｃ、及びＷは、一般式（Ｉ）で定義した通りである）を有する式（Ｉ−ｂ）のアミン化合物を反応させて、式（Ｉ−ｃ）の中間体化合物：

（ここで、Ｘはハロであり、Ｌ^１、Ｒ^１、Ｑ_１、Ｑ_２、Ｑ_３、Ｑ_４、Ｒ^３ａ、Ｒ^３ｃ、及びＷは、一般式（Ｉ）で定義した通りである）を形成する。 Step (1): The following structure:

(Here, X and X'are independent halos, and R ^3a , Q ₁ , Q ₂ , Q ₃ and Q ₄ are as defined by the general formula (I)) (I). -A) compound,
The following structure:

(Here, L ¹ , R ¹ , R ^3c , and W are as defined by the general formula (I)) by reacting the amine compound of the formula (I-b) with the formula (I-c). ) Intermediate compound:

(Here, X is a halo, and L ¹ , R ¹ , Q ₁ , Q ₂ , Q ₃ , Q ₄ , R ^3a , R ^3c , and W are as defined by the general formula (I)). To form.

（ここで、ｄ、ｍ、Ｌ^２、Ｒ^２、及びＲ^３ｂは、一般式（Ｉ）で定義した通りである）を有する式（Ｉ−ｄ）の環状アミノ化合物を反応させる。 Step (2): In the intermediate compound of the formula (I-c), the following structure:

(Here, d, m, L ² , R ² and R ^3b are as defined by the general formula (I)), and the cyclic amino compound of the formula (Id) is reacted.

Scheme I:

Step 1 of the general synthesis method is a standard Buchwald (or Buchwald-Hartwig) amination condition (Buchwald, SL et al.; J. Org. Chem. 2001, 66 (8), 2560-2565; or Buchwald, SL. , et al.,; J. Am. Chem. Soc. 2014, 136, 1617-1627; Surry DS et al. Chemical Science 2011, 2, 27-50), especially palladium acetate (Pd (COAc) ₂ ). In the presence of palladium catalysts such as, ligands, preferably buchwald organic phosphorus ligands such as xanthhos (CAS number: 16126-05-03-8), and bases such as sodium tert-butyl oxide, toluene, tetrahydrofuran (THF), dimethoxy. It can be done in a solvent such as ethane (DME), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), or 1,4-dioxane, and any mixture thereof. .. Step 1 can be carried out at a temperature from room temperature to a maximum of 150 ° C., preferably 70 ° C. to 120 ° C.
Note: Compounds of formula (I-a) (having 2,4-dihalo-quinoline, finally group R ^3a _{and / or one} or more of groups Q 1, Q ₂ , Q ₃ and Q ₄ ) , Commercially available, or can be prepared according to methods known to those of skill in the art.

Step 2 of a general synthesis method can be carried out under various conditions known to those skilled in the art. In particular, the resulting compound (1-b) having a halo (eg, chloro or bromo) substituent at position 4 is N-methyl-2 in the presence of a base such as N, N-diisopropylethylamine (DiPEA). -With compound (1-d) (cyclic secondary amine) in a polar solvent such as pyrrolidone (NMP) under microwave irradiation and at temperatures ranging from 80 ° C to 250 ° C, particularly 120 ° C to 200 ° C. Can be subjected to a nucleophilic aromatic substitution reaction (SNAr). Coupling of compound (1-d) (cyclic secondary amine) with halo compound (1-b) also promotes efficient cross-coupling between the two organic substrates under a palladium (0) catalyst. It can be done in the presence of a suitable phosphine-based ligand. Many variants of the conditions for efficient coupling of complex aromatic halides with amines are known in the chemical literature (eg, Surry DS, Buchwald SL., Chem. Sci., 2011, 2 (eg). 1), see 27-51).

本発明の式（Ｉ）の化合物はまた、反応スキームＩＩに示すように調製することができ、ここで、工程１’及び２’は、それぞれ工程２と１について上記したように行うことができる。 Scheme II:

The compound of formula (I) of the present invention can also be prepared as shown in Reaction Scheme II, where steps 1'and 2'can be performed as described above for steps 2 and 1, respectively. ..

Scheme III:

In some embodiments, the compound of formula (I) (or If) in which ^{R 3c is H is the following alkylating agent: R 3c-} LG (I-g) [where LC is halo. Appropriate leaving (eg, chloro, iodine, bromo), or sulfonic acid ester (eg, trifluoromethanesulfonic acid (triflate), methanesulfonate (mesylate), or p-toluenesulfonate (tocillate)). A group, R ^3c is a substituted or substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, or a substituted or unsubstituted heterocycloalkyl. In the presence of], it can be subjected to an N-alkylation reaction (see Scheme II). According to these embodiments, the N-alkylation reaction is stirred in a reaction-inert organic solvent such as acetonitrile (MeCN) or dimethylformamide (DMF) at a temperature of less than 150 ° C, preferably 25 ° C to 120 ° C. Can be done by. In particular, the N-alkylation reaction is carried out in the presence of a base such as sodium hydride (NaH) and optionally in the presence of an alkali metal iodide (eg KI or NaI).

Note: In some cases, the compounds of formulas (Ia)-(1-f) and / or the alkalizing agent (Ig) may contain one or more specific chemically reactive functional groups (eg, amines, hydroxys, thiols, etc.). It may have (carboxy, aldehyde, etc.) independently, which can compete with the desired reaction and result in undesired side reaction products. Functional group protection strategies can be used to prevent unwanted binding and the formation of side reaction products. This basic protection strategy is known to those of skill in the art. That is, protecting groups can be used to temporarily mask certain chemically reactive functional groups to allow the formation of the desired intermediate or final compound. As used herein, the terms "protected," "protecting group," and "protecting group" are those of a particular chemical reactivity in a molecule under certain reaction conditions. Refers to the presence of a moiety (ie, protecting group) that prevents or blocks the reaction of a functional group. Protecting groups vary depending on the type of chemically reactive group to be protected, as well as the reaction conditions used, and the presence of additional reactive or protecting groups in the molecule, if any. Protecting groups known in the art are found in Greene, T.W., et al., PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 3rd Edition., John Wiley & Sons, Inc., New York, NY (1999).

In the above schemes (I), (II), and (III), starting compounds (eg, compounds (Ia), (Ib), and (Id)), reactants (eg, alkylating agents (1-f)). ), And intermediates, if not described, are commercially available, described in the literature, or described therein, or manufactured according to methods known to those of skill in the art. be able to.

IV. Pharmacology and usefulness Advantageously, the compounds of the present invention exhibit potent growth inhibitory effects on different cancer cell lines. This potent growth inhibitory effect is readily demonstrated by in vitro assays against cancer cell samples such as the following cancer cell lines described herein: hepatocellular carcinoma cells (HepG2 and Huh7), colonic rectal cancer cells (HCT). -116), acute myeloid leukemia (MOLM-14), malignant melanoma cells (A375), pancreatic cancer cells (PANC-1), and renal adenocarcinoma (786-O) cells. The compounds of this invention are generally less than about 10 [mu] M, preferably have an inhibitory values _{EC 50} for less than about 5 [mu] M.

Due to their surprisingly strong anti-cancer activity, the compounds of the present invention can be advantageously administered at lower doses compared to other less potent anti-cancer agents of the prior art, but are still equivalent or better. Achieve the desired biological effect. Moreover, such dose reductions may advantageously have little or no medical adverse effects. Moreover, the high inhibitory effects of the compounds of the invention can, by themselves, reduce unwanted side effects, regardless of the dose applied.

That is, the compounds of the present invention are considered to be effective against cell proliferation diseases that can be caused by neobiological or non-neoplastic disorders in individuals.

The compounds of the present invention are also believed to be effective against drug-resistant or radiation-resistant cancers.

It is believed that the compounds of the present invention can also result in cancer regression and enhance the viability of cancer patients.

In addition, the compounds of the invention can also be used to sensitize a subject to other therapies such as radiation therapy, or as maintenance therapy for cancer patients.

Accordingly, the invention also comprises a compound of formula I, or formula II, or formula III, or formula III', or formula IV for use as a pharmaceutical, or a pharmaceutically acceptable salt or hydrate thereof, respectively. Provided are solvates, or prodrugs, or isotopic variants, tautomers, or stereoisomers. Such medicines can be specifically aimed at treating or preventing diseases in mammals.

The invention also relates to the use of a compound of formula (I) as defined above for preparing a pharmaceutical for the treatment of proliferative disorders, which can be selected from neoplastic and non-neoplastic diseases.

Proliferative disorders treated according to the present invention are preferably neoplastic or non-neoplastic diseases. In particular, neoplastic diseases include cancer, tumor, malignant tumor, malignant lymphoma, malignant melanoma, malignant stellate cell tumor, benign tumor, solid tumor, sarcoma, cancer, hyperproliferative disease, myeloid proliferative disease, cartinoid, Ewing sarcoma, Kaposi sarcoma, brain tumor, tumor derived from brain and / or nervous system and / or medullary membrane, neuroblastoma, neuroblastoma, neuroblastoma, gastric cancer, pancreatic cancer, kidney cancer, renal cell cancer, prostate cancer, binding Tissue tumor, soft tissue sarcoma, fibrosarcoma, pancreatic tumor, liver tumor, head tumor, cervical tumor, laryngeal cancer, nasopharyngeal cancer, esophageal cancer, colon cancer, thyroid cancer, osteosarcoma, retinalblastoma, thoracic adenoma, Testis cancer, lung cancer, lung adenocarcinoma, small cell lung cancer, bronchial cancer, breast cancer, intestinal cancer, colon-rectal cancer, colon cancer, prostate cancer, rectal cancer, gynecological tumor, ovarian tumor, uterine cancer, cervical cancer, uterine body Cancer, papillary cancer, endometrial cancer, bladder cancer, urogenital cancer, skin cancer, epithelial tumor, squamous epithelial cancer, basal cell cancer, basal cell cancer, myeloma, melanoma, intraocular melanoma, leukemia, monosphere Leukemia, Chronic Leukemia, Chronic myeloid leukemia, Chronic lymphocytic leukemia, Acute leukemia, Acute myeloid leukemia, Acute premyelocytic leukemia (APL), Acute lymphocytic leukemia, Acute T-cell lymphoblastic leukemia, Adult T-cell Leukemia, basal leukemia, eosinophil leukemia, granulocytic leukemia, hair cell leukemia, leukocyte depletion leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, macronuclear leukemia, small A cancer selected from the group consisting of blastic leukemia, monocytic leukemia, neutrophil leukemia, stem cell leukemia, germ cell cancer, metastatic proliferation, and other neoplastic diseases known to those of skill in the art.

In general, metastasis of any cancer can be prevented or treated with the compounds of the invention.

Representative examples of non-neoplastic disorders are, but are not limited to, benign tumors, psoriasis, benign proliferative skin diseases, fish scales, papilloma, re-stenosis, scleroderma and hemangiomas, and. White plate disease, rheumatoid arthritis, ischemia-reperfusion-related cerebral edema and injury, cortical ischemia, ovarian hyperplasia and hypervasion, (polycystic ovary syndrome), endometriosis, diabetic retinopathy, and other eyes Angiogenic diseases such as premature infant retinopathy (posterior crystal fibroproliferative disorder), luteal degeneration, corneal transplant rejection, neuroblastic glaucoma, and Osterweber syndrome, ophthalmic disease, choroidal angiogenesis, diabetic retinopathy, inflammation. Includes sexual disorders, arthritis, neurodegeneration, transplant rejection, fibrosis, restenosis, atherosclerosis, inflammation, impaired wound healing, and angiogenesis, as well as other non-neoplastic disorders known to those of skill in the art. ..

Neoplastic diseases are, in particular, liver cancer, pancreatic cancer, lung cancer, bladder cancer, colorectal cancer, acute myeloid leukemia, malignant melanoma, renal adenocarcinoma, and gastrointestinal cancer (esophageal cancer, gastric cancer, small bowel cancer, colorectal cancer). , Rectal cancer, and colon cancer). In particular, neoplastic diseases are liver cancers selected from the group of hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma.

The compound showed high inhibitory activity against different liver cancer cell lines (eg, HepG2 or Huh7). Accordingly, an object of the present invention is, in particular, the use of a compound of formula (I) as defined above for preparing a pharmaceutical for the treatment of a neoplastic disease, wherein the neoplastic disease is hepatocytes. Kidney cancer selected from carcinoma, cholangiocarcinoma, and hepatoblastoma.

In addition, the compounds of the invention may also be suitable for targeting and killing cancer stem cells (CSCs). Accordingly, the present invention is also used to inhibit the proliferation or differentiation of cancer stem cells (CSCs), tumor-initiating cells, cancer-related mesenchymal cells, mesenchymal cancer cells, or mesenchymal cells. Formula I, or Formula II, or Formula III, or Formula III', or a compound of Formula IV, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug, or an isotope variant thereof. , Mutual mutants, or steric isomers.

The compounds of the present invention may also be useful in inhibiting the recurrence of cancer, especially in the liver and pancreas.

V. Pharmaceutical composition-formulation-kit:
The compounds of the invention can be incorporated into compositions (see "Pharmaceutical Compositions" section below). Optionally, the composition may contain one or more additional active substances (see "Pharmaceutical Compositions" section below). The pharmaceutical composition and drug combination can be in any suitable form (depending on the desired route of administration to the individual).

Pharmaceutical composition:
Accordingly, in another aspect, the invention also provides a pharmaceutical composition comprising one or more of the compounds of the invention as an active ingredient. Typically, the compounds of the invention used as active ingredients are formulated with one or more pharmaceutically acceptable carriers (eg, excipients, diluents, or adjuvants). Generally, the compound of the present invention is present in a therapeutically effective amount as an active ingredient in the pharmaceutical composition of the present invention.

As described in detail below, the pharmaceutical compositions of the invention can be formulated specifically for administration in solid or liquid form, including those suitable for: (1) oral administration, eg, drinking. Drugs (aqueous or non-aqueous solutions or suspensions), tablets, such as those targeted for cheek, sublingual, and systemic absorption, bolus, powders, granules, pastes for application to the tongue, (2) non. Oral administration, eg, parenteral administration by subcutaneous, intramuscular, intravenous, or epidural injection as a sterile solution or suspension or sustained release formulation; (3) Topical application, eg cream, ointment, or controlled release patch. Or applied to the skin as a spray; (4) intravaginally or in the rectum, eg as a pessary, cream, or foam; (5) sublingual; (6) eye; (7) transdermally; (8) Administer to the nose; (9) to the lungs; or (10) intrathecal.
As used herein, the phrase "therapeutically effective amount" is effective in producing any desired therapeutic effect in at least a subpopulation of animal cells at a reasonable benefit / risk ratio applicable to any medical procedure. It means the amount of a compound, a material, or a composition containing the compound of the present invention.
Representative examples of materials that can serve as pharmaceutically acceptable carriers are not particularly limited, but are: (1) sugars such as lactose, glucose and sucrose; (2) starch such as corn starch and Potato starch; (3) cellulose such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate, and derivatives thereof; (4) powdered tragacant; (5) malt; (6) gelatin; (7) talc; (8) shaping. Agents such as cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, Benibana oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin. , Sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate, ethyl laurate; (13) agar; (14) bulking agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) ) Heat-free water; (17) isotonic physiological saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH-buffered solution; (21) polyester, polycarbonate, and / or polyanhydrous (22) Includes other non-toxic compatible substances used in pharmaceutical formulations.
Also in the composition are wetting agents, emulsifying agents and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colorants, mold release agents, coating agents, sweetening agents, flavoring agents and fragrances, preservatives. And antioxidants may also be present.
Examples of pharmaceutically acceptable antioxidants include (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bicarbonate, sodium metabisulfate, sodium sulfite; (2) fat-soluble antioxidants. , For example ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol; and (3) metal chelating agents such as citric acid, ethylenediamine tetraacetic acid (EDTA). , Sorbitol, tartrate acid, phosphoric acid.
The formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, and / or parenteral administration. The pharmaceuticals are conveniently provided in unit dosage form and can be prepared by any method known in the pharmaceutical art. The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. The amount of active ingredient that can be combined with the carrier material to produce a single dosage form is generally the amount of compound that produces a therapeutic effect. Generally, this amount is about 0.1% to about 99% of the active ingredient out of 100%, preferably about 5% to about 70%, most preferably about 10% to about 30%.
In certain embodiments, the formulations of the invention are the excipients selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle-forming agents such as bile acids, and polymer carriers such as polyesters and polyanhydrides. Including the compound of the invention. In certain embodiments, the pharmaceuticals make the compounds of the invention bioavailable orally.
The method for preparing these formulations or compositions comprises the step of associating the compound of the invention with a carrier and optionally one or more auxiliary components. Generally, a pharmaceutical product is prepared by uniformly and closely associating the compound of the present invention with a liquid carrier and / or a finely divided solid support, and then molding a product if necessary.
Suitable for oral administration, the formulations of the present invention are in the form of capsules, cashews, pills, tablets, lozenges (using flavored bases, usually syrup, and acacia, or tragacant), powders, granules. , Or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or a troche (inert bases such as gelatin and glycerin, Or using syrup and acacia), and / or as an oral cleaning agent, etc., each containing a predetermined amount of the compound of the present invention as an active ingredient. The compounds of the invention can also be administered as bolus, licking agent, or paste.
In the solid dosage form of the invention for oral administration (capsules, tablets, rounds, sugar-coated tablets, powders, granules, touch agents, etc.), the active ingredient is one or more pharmaceutically acceptable carriers such as stearic acid. Sodium or dicalcium phosphate and / or any of the following (1) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and / or silic acid; (2) binders such as carboxy Methylcellulose, alginate, gelatin, polyvinylpyrrolidone, sculose, and / or acacia; (3) wetting agents such as glycerol; (4) disintegrants such as agar-agar, calcium carbonate, potato starch or tapioca starch, alginic acid, specific Sirates and sodium carbonate; (5) dissolution retarders such as paraffin; (6) absorption enhancers such as quaternary ammonium compounds and surfactants such as poroxamer and sodium lauryl sulfate; (7) wetting agents such as Cetyl alcohol, glycerol monostearate, and nonionic surfactants; (8) absorbents such as kaolin and bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, lauryl It is mixed with sodium sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) colorants; and (11) controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets, and pills, the pharmaceutical composition may also include a buffer. Similar types of solid compositions can also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or lactose as well as high molecular weight polyethylene glycol.
Tablets can be produced by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets are binders (eg gelatin or hydroxypropylmethyl cellulose), lubricants, inert diluents, preservatives, disintegrants (eg sodium starch glycolate or crosslinked sodium carboxymethyl cellulose), surfactants, or dispersions. It can be prepared using an agent. Molded tablets can be produced by molding a mixture of powdered compounds moistened with an inert liquid diluent on a suitable machine.
The tablets and other dosage forms of the pharmaceutical compositions of the invention, such as sugar-coated tablets, capsules, pills, and granules, may optionally be coated with enteric coatings and other coatings well known in the pharmaceutical art. The shell is used to make or prepare cuts. They are also prepared using, for example, hydroxypropylmethylcellulose in various proportions to provide sustained release or controlled release of the active ingredient therein, with the desired release profile, other polymer matrix, liposomes, and. / Or a microsphere can also be provided. They may be prepared for rapid release, eg lyophilized. They can be sterilized, for example, by filtering with a bacterial retention filter or by incorporating a sterile agent in the form of a sterile solid composition that can be dissolved in sterile water or other sterile injectable medium immediately prior to use. These compositions may also optionally contain a milky whitening agent and may be a composition that optionally releases only the active ingredient, or preferentially, in certain parts of the gastrointestinal tract, optionally delayed. .. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, optionally using one or more of the above excipients.
Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, liquids, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage form is an inert diluent commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, acetic acid. Ethyl, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol , And sorbitan fatty acid esters, and mixtures thereof.
In addition to the Inactive Diluent, the oral composition can also include adjuvants such as wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, coloring agents, fragrances, and preservatives.
Suspensions, in addition to active compounds, include suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metal hydroxide, bentonite, agar-agar, and tragant. And may contain mixtures thereof.
Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration can be provided as suppositories, which can be added to one or more compounds of the invention, eg, cocoa butter, polyethylene glycol, suppository wax, etc. Alternatively, it can be prepared by mixing one or more suitable non-irritating excipients or carriers containing salicylate, which is solid at room temperature but liquid at body temperature and thus rectal or vaginal. It dissolves in and releases the active compound.
Formulations of the invention suitable for intravaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing carriers known to be suitable in the art.
Dosage forms for topical or transdermal administration of the compounds of the invention include powders, sprays, ointments, pastes, creams, lotions, gels, liquids, patches and inhalants. The active compound can be mixed with a pharmaceutically acceptable carrier and any preservative, buffer, or propellant that may be needed under sterile conditions.
Ointments, pastes, creams, and gels, in addition to the active compounds of the invention, include excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacants, cellulose derivatives, polyethylene glycols, silicones, bentonites, kay. It can contain acids, talc, and zinc oxide, or mixtures thereof.
In addition to the compounds of the invention, the powders and sprays can contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. The spray can further include conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.
Transdermal patches have the additional advantage of providing controlled delivery of the compounds of the invention into the body. Such dosage forms can be made by dissolving or dispersing the compound in a suitable medium. Absorption enhancers may also be used to increase the flow rate of the compound through the skin. The velocity of such a flow can be controlled by providing a velocity control membrane or by dispersing the compound in a polymer matrix or gel.
Ophthalmic preparations, ophthalmic ointments, powders, liquids and the like are also considered to be within the scope of the present invention.
The pharmaceutical composition of the present invention suitable for parenteral administration is a sterile, isotonic, aqueous or non-aqueous solution, dispersion, which contains one or more compounds of the present invention pharmaceutically acceptable. Containing in combination with a suspension or emulsion, or a sterile powder that can be restored with a sterile injectable solution or dispersion immediately before use, which includes sugars, alcohols, antioxidants, buffers, bacteriostatic agents, It may contain a solute, or suspension or thickener, that makes the formulation isotonic with the blood of the intended receptor.
Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (eg, glycerol, propylene glycol, polyethylene glycol), and suitable mixtures thereof, vegetable oils, eg. Includes olive oil and injectable organic esters such as ethyl oleate. Appropriate fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain auxiliary agents such as preservatives, wetting agents, emulsifying agents, and dispersants. Prevention of microbial action on the compound of interest can be ensured by including various antibacterial and antifungal agents such as parabens, chlorobutanol, phenolsorbic acid and the like. It may also be desirable to include isotonic agents (eg sugar, sodium chloride) in the composition. In addition, long-term absorption of the injectable pharmaceutical form can be brought about by the inclusion of drugs that delay absorption, such as aluminum monostearate and gelatin.
In some cases, it is desirable to delay the absorption of the drug by subcutaneous or intramuscular injection in order to sustain the action of the drug. This can be achieved by the use of low water solubility crystalline or amorphous liquid suspensions. Second, the rate of absorption of the drug depends on its rate of dissolution, which may depend on its crystal size and crystal morphology. Alternatively, delayed absorption of the dosage form administered parenterally is achieved by dissolving or suspending the drug in an oily vehicle.
The injectable depot form is created by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the drug-to-polymer ratio and the nature of the particular polymer used. Examples of other biodegradable polymers include poly (orthoester) and poly (anhydride). Depot injection formulations are also prepared by encapsulating the drug in liposomes or microemulsions that are compatible with body tissue.
When the compound of the present invention is administered as a pharmaceutical product to a subject (eg, human or animal) in need, it is administered by itself or, for example, 0.1 to 99% (more preferably 10 to 30%). It can be administered as a pharmaceutical composition containing the active ingredient in combination with a pharmaceutically acceptable carrier.
The pharmaceutical product of the present invention can be administered orally, parenterally, topically, or rectally. They are, of course, administered in a form suitable for each route of administration. For example, they are tablets or capsules, by injection, inhalation, eye drops, ointments, suppositories, etc., by injection, infusion, or inhalation; locally by lotion or ointment; orally administered by suppository, rectal. Administration is preferred.

As used herein, the terms "parenteral administration" and "administered parenterally" refer to modes of administration other than enteral and topical administration by conventional injection, and are not particularly limited. Intravenous, intramuscular, arterial, intramedullary, intracapsular, intraocular, intracardiac, intracutaneous, intraperitoneal, enteral, subcutaneous, subepithelial, intravaginal, subcapsular, submucosal, spinal cord, and thoracic bone Includes injections and infusions within.
As used herein, the terms "systemic administration,""systemicadministration,""peripheraladministration," and "peripheral administration" refer to compounds, drugs, or other substances in the central nervous system. It means administration other than direct administration to the system, and thus it enters the patient's system and is therefore subject to metabolism and other similar processes such as subcutaneous administration.
These compounds can be given to the required subject (eg, human or animal), eg, orally, eg, by spray, nasally, rectal, vaginal, parenteral, intracapsular, and as a powder, as an ointment, or as a drop. The agent can be administered by an appropriate route of administration, including topical administration (including cheek and sublingual).
Regardless of the route of administration selected, the compounds of the present invention and / or the pharmaceutical compositions of the present invention which can be used in a suitable hydrated form are pharmaceutically acceptable dosage forms according to conventional methods known to those skilled in the art. It is formulated in. The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention is an amount effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without toxicity to the patient. Can vary to obtain the active ingredient.
The dose level selected is first to the subject to be treated (human or animal) and to the particular compound of the invention being used, or a pharmaceutically acceptable salt, hydrate, solvate thereof. It depends on the activity of the compound, prodrug, isotope variant, tautomer, or stereoisomer thereof. When the pharmaceutical composition is administered to a human individual, the daily dose is usually determined by the prescribing physician and the dose is generally the individual's age, gender, diet, weight, general health, and response, individual. The severity of the symptoms, the exact indication or condition to be treated, the severity of the exact indication or condition to be treated, the time of administration, the route of administration, the nature of the composition, the rate of excretion, the combination of drugs, and It depends on the discretion of the prescribing physician. The route of administration can also vary depending on the condition and its severity. Preferably, the pharmaceutical composition is in unit dosage form. In such a form, the preparation is subdivided into unit doses containing the appropriate amount of active ingredient, eg, an amount effective to achieve the desired purpose. Determining the appropriate dosage for a particular situation is within the skill of one of ordinary skill in the art. Treatment is generally initiated at a dose lower than the optimal dose of the compound. Then, the dose is increased in small doses until the optimal effect is reached in that situation. For convenience, if necessary, the total daily dose may be divided and administered in divided doses during the day. The dosage and frequency of the compounds described herein, and if applicable, other therapeutic agents and / or treatments, are adjusted according to the discretion of the attending clinician (physician) in consideration of the factors described above. .. Therefore, the amount of pharmaceutical composition administered can vary widely.
Administration is carried out at about 0.001 mg / kg body weight to about 100 mg / kg body weight / day (single or divided doses), more preferably at least about 0.1 mg / kg body weight / day. The particular therapeutic dose comprises, for example, from about 0.01 mg to about 7000 mg of the compound, preferably including, for example, from about 0.05 mg to about 2500 mg. More specifically, in the case of oral or parenteral administration of an adult weighing about 70 kg, 0.1 mg to 5 g, preferably about 0.1 mg to 1 g, more preferably 0.5 mg to 500 mg, most preferably about. Daily doses ranging from 1 mg to 300 mg are appropriate, but may exceed the upper limit if necessary. The amount of active compound in a unit dose preparation can be varied or adjusted from about 0.1 mg to 1000 mg, preferably from about 1 mg to 300 mg, more preferably from 10 mg to 200 mg, depending on the particular application. In some cases, dose levels below the lower limit of the above range are more than adequate, in other cases higher doses may be given in several divided doses to administer throughout the day. Allows it to be used without causing harmful side effects. The quantity to be administered will vary depending on the particular IC ₅₀ value or EC ₅₀ value of the compound used. In combination applications where the compound is not the only treatment, it is possible to administer smaller amounts of the compound and may still have a therapeutic or prophylactic effect. If desired, the effective daily dose of the active compound is administered separately at appropriate intervals throughout the day, optionally in unit dosage form, as a supplementary dose of 2, 3, 4, 5, 6 or more. be able to. The preferred administration is once daily.
Although the compound of the present invention can be administered alone, it is preferably administered as a pharmaceutical preparation (composition). The compounds of the invention, like any other drug, can be formulated for administration in any convenient way for use in human or veterinary drugs.

In another aspect, the invention comprises a therapeutically effective amount of one or more of the above-mentioned compounds of the invention formulated with one or more pharmaceutically acceptable carriers (additives) and / or diluents. The composition is provided. As described in detail below, the pharmaceutical compositions of the invention can be formulated specifically for administration in solid or liquid form, including those adapted as follows: (1) Oral administration. Subcutaneous, eg, as a drench (aqueous or non-aqueous solution or suspension), tablets, bolus, powders, granules, pastes for application to the tongue, (2) parenteral administration, eg sterile solutions or suspensions. , Intramuscular or parenteral administration by intravenous injection; (3) Topical application, eg, cream, ointment, or spray applied to the skin, lungs, or mucous membranes; (4) Intravaginal or rectal administration, eg, pessary. , Cream, or foam; (5) sublingual or cheek; (6) eye; (7) transdermally; (8) nasal administration.

The compound of the present invention can be administered as it is or in combination with a pharmaceutically acceptable carrier, and can also be administered in combination with antibacterial agents such as penicillin, cephalosporins, aminoglycosides, and glycopeptides. .. Combination therapy thus comprises sequential, simultaneous, and separate administration of the active compound in such a way that the therapeutic effect of the first dose does not completely disappear when the next compound is administered.
Microemulsification techniques can improve the bioavailability of some lipophilic (water-insoluble) agents. Examples include Trimetrine (Dordunoo, SK, et al., Drug Development and Industrial Pharmacy, 17 (12), 1685-1713, 1991) and REV5901 (Sheen, P. C, et al., J Pharm Sci). There are 80 (7), 712-714, 1991). In particular, microemulsification results in improved bioavailability by prioritizing absorption into the lymphatic system instead of the circulatory system, thereby bypassing the liver and preventing compound destruction in the hepatobiliary circulation. All suitable amphipathic carriers are intended, but currently preferred carriers have a "Generally Recognized-as-Safe" (GRAS) condition. The compounds of the invention can be solubilized and microemulsified after the solution is later contacted with a complex aqueous phase (eg, one found in the human gastrointestinal tract). .. Usually, amphipathic components that meet these requirements have HLB (hydrophilic to lipophilic balance) values of 2 to 20, and their structures are linear fats in the range C-6 to C-20. Contains group groups. Examples are polyethylene glycolated fatty glycerides and polyethylene glycol. Commercially available amphipathic carriers are specifically contemplated, such as the Gelucire series, Labrafil, Labrasol, or Lauroglycol (all manufactured and sold by Gattefosse Corporation, Saint Priest, France), PEG-monooleate, PEG-geolate, PEG-mono. Laurate and dilaurate, lecithin, polysorbate 80, etc. (manufactured and sold by many companies in the United States and around the world).
Hydrophilic polymers suitable for use in the present invention are readily water soluble, covalently attached to vesicle-forming lipids, and tolerated in vivo (ie, biocompatible) without toxic effects. Suitable polymers include polyethylene glycol (PEG), polylactic acid (also referred to as polylactide), polyglycolic acid (also referred to as polyglycolide), polylactic acid-polyglycolic acid copolymer, and polyvinyl alcohol. The trowel polymer is a polymer having a molecular weight from about 100 or 120 daltons to about 5,000 or 10,000 daltons, more preferably from about 300 daltons to about 5,000 daltons. In a particularly preferred embodiment, the polymer is polyethylene glycol having a molecular weight of about 100 to about 5,000 Dalton, more preferably about 300 to about 5,000 Dalton. In a particularly preferred embodiment, the polymer is 750 Dalton polyethylene glycol (PEG-750). Polymers can also be defined by the number of monomers in them. A preferred embodiment of the invention utilizes a polymer of at least about 3 monomers, eg, a PEG polymer consisting of 3 monomers (about 150 daltons). Other hydrophilic polymers suitable for use in the present invention include polyvinylpyrrolidone, polymethoxazoline, polyethyloxazoline, polyhydroxypropylmethacrylamide, polymethacrylamide, polydimethylacrylamide, and derivatized celluloses such as hydroxymethylcellulose or hydroxyethylcellulose. Is included.
In certain embodiments, the formulations of the invention are polyamides, polycarbonates, polyalkylenes, acrylic and methacrylic ester polymers, polyvinyl polymers, polyglycolides, polysiloxanes, polyurethanes and copolymers thereof, celluloses, polypropylenes, polystyrenes, lactic acid and glycols. Acid polymers, polyacid anhydrides, poly (ortho) esters, poly (butyric acid), poly (valeric acid), poly (lactide-co-caprolactone), polysaccharides, proteins, polyhyaluronic acid, polycyanoacrylate, and these. Includes blends, mixtures, or copolymers of.
Cyclodextrins are cyclic oligosaccharides consisting of 6, 7, or 8 glucose units, represented by the Greek letters alpha, beta, or gamma letters, respectively. It is known that there are no cyclodextrins with less than 6 glucose units. Glucose units are linked by α-1,4-glucosidic bonds. As a result of the chair-shaped configuration of sugar units, all secondary hydroxyl groups (C-2, C-3) are located on one side of the ring and all primary hydroxyl groups on C-6 are on the other side. To position. As a result, the outer surface becomes hydrophilic, making cyclodextrin water-soluble. In contrast, cyclodextrin cavities are hydrophobic because they are lined with hydrogen and ether-like oxygen at the C-3 and C-5 atoms. These matrices allow complexing with various relatively hydrophobic compounds, including, for example, steroid compounds such as 17β-estradiol (eg, van Uden et al. Plant Cell Tiss. Org. Cult. 38: 1-3-113 (1994)). Complexity occurs by van der Waals interactions and hydrogen bond formation. For a general review of cyclodextrin chemistry, see Wenz, Agnew. Chem. Int. Ed. Engl., 33: 803-822 (1994).
Liposomes consist of at least one lipid bilayer membrane that surrounds the aqueous inner compartment. Liposomes can be characterized by the type and size of the membrane. Small single lamellar vesicles (SUVs) have a single membrane, typically in the range 0.02-0.05 μm in diameter, and large single lamellar vesicles (LUVs) are typical. Is larger than 0.05 μm. Large and multi-lamella vesicles of oligolamella have multiple normally concentric membrane layers, typically larger than 0.1 μm. Liposomes with several non-concentric membranes, i.e., some smaller vesicles contained within larger vesicles, are called polyvesicles.

One aspect of the invention relates to a formulation comprising liposomes containing a compound of the invention, wherein the liposome membrane is formulated to provide a liposome with an increased carrying capacity. Alternatively, or further, the compound of the invention may be contained or adsorbed within the liposome bilayer of the liposome. The compound of the present invention can be aggregated with a lipid surfactant and carried into the internal space of the liposome. In these cases, the liposome membrane is prepared to resist the destructive action of the active agent-surfactant aggregate.
In one embodiment of the invention, the lipid bilayer of the liposome comprises a lipid derivatized with polyethylene glycol (PEG), so that the PEG chain is from the inner surface of the lipid bilayer into the internal space encapsulated by the liposome. It extends from the outside of the lipid bilayer to the surrounding environment. The active agent contained in the liposome of the present invention is in a solubilized form. Aggregates of detergent and active agent (eg, emulsions or micelles containing the active agent of interest) may be trapped within the interior space of the liposomes of the invention. Surfactants act to disperse and solubilize the active agent and, without limitation, biocompatible lysophosphatidylcholine (LPC) of various chain lengths (eg, from about C ₁₄ to about C). ₂₀ ) can be selected from any suitable aliphatic, alicyclic, or aromatic surfactant. Polymer derivatized lipids such as PEG-lipids also act to inhibit micelle / membrane fusion, and the addition of the polymer to the detergent molecule lowers the CMC of the detergent and aids in micelle formation. It can be used for formation. Surfactants with a micromolar range of CMC are preferred. Higher CMC surfactants can be used to prepare micelles confined within the liposomes of the invention, but micelle surfactant monomers affect liposome double layer stability and desired stability. Will be a factor in designing liposomes with.
The liposome of the present invention can be prepared by any of various techniques known in the art. For example, US Pat. No. 4,235,871; Published PCT Application International Publication No. 96/14057; New RRC, Liposomes: A practical approach, IRL Press, Oxford (1990), pages 33-104; Lasic DD, Liposomes from See physics to applications, Elsevier Science Publishers BV, Amsterdam, 1993.
For example, the liposome of the present invention is a liposome obtained by derivatizing a lipid derivatized with a hydrophilic polymer in a preformed liposome, for example, in a micelle made of a lipid grafted polymer. It can be prepared by exposure at the desired lipid concentration within the liposome, corresponding to the final mol percent. Liposomes containing hydrophilic polymers can also be formed by homogenization, lipid-field hydration, or extrusion techniques, as is known in the art.
In particular, liposomes are prepared to have a substantially homogeneous size in the selected size range. One effective sizing method is to extrude an aqueous suspension of liposomes through a series of polycarbonate membranes with selected uniform pore sizes. The pore size of the membrane roughly corresponds to the largest size liposome produced by extrusion through the membrane. See, for example, US Pat. No. 4,737,323 (April 12, 1988). The release characteristics of the pharmaceutical product of the present invention depend on the encapsulation material, the concentration of the encapsulated drug, and the presence of the release modifier. For example, the release can be engineered to be pH dependent using a pH sensitive coating that releases only at low pH, such as in the stomach or only at higher pH, such as in the intestine. An enteric coating can be used to prevent the release until it has passed through the stomach. Multiple coatings or mixtures of cyanamide encapsulated in different materials can be used to be released first in the stomach and then in the intestine. Release can also be engineered by the inclusion of salts or pore-forming agents that can increase the uptake or release of water by diffusion from the capsule. Excipients that modify the solubility of the drug can also be used to control the rate of release. Agents that enhance matrix degradation or release from the matrix can also be incorporated. They can be added to the drug, can be added as separate phases (ie, as particulates), or can be compound-dependently co-dissolved in the polymer phase. In all cases, the amount should be 0.1 to 30 percent (w / w polymer). Types of decomposition accelerators include inorganic salts such as ammonium sulfate and ammonium chloride, organic acids such as citric acid, benzoic acid, and ascorbic acid, inorganic bases such as sodium carbonate, potassium carbonate, calcium carbonate, zinc carbonate, and hydroxylated. Includes zinc, organic bases such as protamine sulfate, spermin, choline, ethanolamine, diethanolamine, and triethanolamine, as well as surfactants such as Tween® and Pluronic®. A pore-forming agent (ie, a water-soluble compound such as an inorganic salt and a sugar) that adds a microstructure to the matrix is added as fine particles. The range should be 1-30 percent (w / w polymer).
Uptake can also be manipulated by varying the residence time of the particles in the intestine. This can be achieved, for example, by coating the particles with a mucosal adhesive polymer or by selecting as an encapsulation material. For example, most polymers with free carboxyl groups, such as chitosan, cellulose, especially polyacrylates (as used herein, polyacrylates are polymers containing acrylate and modified acrylate groups, such as cyanoacrylates and Refers to methacrylate).

Combination of Pharmaceuticals Further, the compound of the present invention is one or more other active agents (ingredients, drugs) in treating, preventing, suppressing, or ameliorating a disease or condition in which the compound of the present invention or another active agent has usefulness. Can be used in combination with.

Typically, the drug combination is safer or more effective than any drug alone, or the combination is safer than expected based on the additional properties of the individual drugs. It is more effective. Such other drugs can be administered simultaneously or sequentially with the compounds of the invention by commonly used routes and amounts. When the compound of the present invention is used at the same time as one or more other drugs, a combination product containing such another drug and the compound of the present invention is preferable. However, combination therapy also includes treatments in which the compounds of the invention and one or more other drugs are administered on different overlapping schedules. When used in combination with other active ingredients, it is contemplated that the compounds of the invention and / or other active ingredients may be effectively used at lower doses than when each is used alone. Therefore, the pharmaceutical composition of the present invention may contain one or more other active agents in addition to the compound of the present invention.

In certain embodiments, additional active agents that can be included in the pharmaceutical compositions of the invention are for the treatment of cancer. Preferably the additional agent is selected from the following classes of anti-cancer agents: BCPv-ABL inhibitor, ALK inhibitor, BRAF inhibitor, FLT3 inhibitor, MEK inhibitor, vascular endothelial growth factor (VEGF) receptor inhibitor. , HER2 receptor inhibitor, CD20 antibody, tyrosine kinase inhibitor, DNA synthesis inhibitor, anti-neoplastic agent, epidermal growth factor receptor (EGFR) inhibitor, HER dimerization inhibitor, human granulocyte colony stimulator (G-CSF) regulator, immunomodulator, CD40 inhibitor, pro-appropriate receptor agonist (PARA) hedgehog antagonist, PI3K inhibitor, phosphorlipase A2 inhibitor, BCL-2 inhibitor, mitogen-activated protein kinase kinase ( MEK) Inhibitors, Aromatase Inhibitors, Topoisomerase I Inhibitors, Topoisomerase II Inhibitors, mTOR Inhibitors, Osteocellular Bone Resorption Inhibitors, CD33 Antibody Drug Inhibitors, CD22 Antibody Drug Inhibitors, CD20 Antibody Drug Inhibitors, Somatostein analog, synthetic interleukin-11 (IL-11), synthetic erythropoetin, nuclear factor κB receptor activator (RANK) inhibitor, thrombopoetin mimic peptibody, cell proliferation stimulant, antiinsulin-like proliferation factor-1 receptor (IGF-1R) antibody, anti-CS1 antibody, CD52 antibody, CTLA-4 inhibitor, histone deacetylase inhibitor (HDI), alkylating agent, biological response regulator, antitumor antibiotic, antimicrotube Agents, catepsin K inhibitors, epotiron B analogs, heat shock protein (HSP) inhibitors, TpoR agonists, anti-thread splitting agents, adrenal steroid inhibitors, anti-androgen agents, androgen, proteasome inhibitors, CDK1 inhibitors, gonadotropins Release hormone (GnRH) receptor agonist, taxan anti-neoplastic agent, 5HT1a receptor agonist, HPC vaccine, iron chelating agent, metabolic antagonist, bisphosphonate, demethylating agent, plant alkaloid, glucocorticosteroid, cytokine, estrogen acceptance Body down regulators, anti-estrogen, selective estrogen receptor regulators (SERMs), luteinizing hormone-releasing hormone (LHRH) agonists, progesterone, and other cytotoxic agents.

Specific examples of each of these classes of anticancer agents are shown in Table 4 below:

The compounds of formula (I) of the invention can also be used in combination with the following adjuvant therapies:
-Anti-nausea: NK-1 receptor antagonist: Casopitant (trade name Rezonic® and Zunrisa® sold by GlaxoSmithKline); and-Cell protectant: Amifostine (trade name Ethyol®) , Leucovorin (also known as leucovorin calcium, citrobum factor, and folinic acid);

Reference references made within this disclosure should not be understood as recognizing that the cited references are prior art that adversely affects the patentability of the invention.

In another aspect of the kit, the invention is an addition to (a) a compound of the formula of the invention; (b) an additional pharmaceutical composition used simultaneously, separately or sequentially to treat cancer. The present invention relates to a kit containing an active substance (for example, an anticancer agent).

In another aspect of treatment, the invention also comprises administering to a patient in need of treating a proliferative disease a therapeutically effective amount of a compound of formula I, formula II, formula III, or formula IV. A method for treating the above-mentioned diseases is provided.

The present invention also provides a method for treating a neoplastic disease such as a tumor, which comprises administering a therapeutically effective amount of the compound of the present invention or the pharmaceutical composition of the present invention to a patient. do.

The present invention also provides a method for treating a non-neoplastic disease, which comprises administering a therapeutically effective amount of the compound of the present invention or the pharmaceutical composition of the present invention to a patient in need.

The following examples are provided to help you better understand the invention. These examples are for illustrative purposes only and should by no means be construed as limiting the scope of the invention. All publications referred to herein are incorporated herein by reference in their entirety.

V. Example I. Chemistry Synthetic Materials and Methods Chemistry
Abbreviations and acronyms A comprehensive list of abbreviations used by those skilled in the art of organic chemistry can be found in The ACS Style Guide (3rd Edition) or the Guidelines for Authors for the Journal of Organic Chemistry. The abbreviations included in the list and all abbreviations used by those skilled in the art of organic chemistry are incorporated herein by reference. For the purposes of the present invention, chemical elements are specified according to the Periodic Table of the Elements, CAS Edition, Handbook of Chemistry and Physics, 67th Edition, 1986-87.

More specifically, when the following abbreviations are used throughout this disclosure, they have the following meanings:
AcOEt: Ethyl acetate;
Ar: Argon Boc or BOC: tert-butyloxycarbonyl DCM: dichloromethane DIAD: Diisopropylazodicarboxylate DiPEA: N, N-diisopropylethylamine DMF: N, N-dimethylformamide Et ₂ O: Diethyl ether ES +: Electron spray ionized HCl : Hydrochloride HMBC: Heteronuclear multiple bond correlation, nuclear magnetic resonance HPLC: High performance liquid chromatography MeCN: acetonitrile MS: mass spectrum, mass analysis MTBE: methyl tert-butyl ether NMP: N-methyl-2-pyrrolidinone NMR: nuclear magnetic resonance experiment RT: Room temperature UPLC: Ultra-high performance liquid chromatography THF: acetonitrile TLC: Thin layer chromatography
¹ HNMR: Proton nuclear magnetic resonance
¹³ C NMR: Carbon nuclear magnetic resonance Δ: Reflux g: Gram h: Time M: Mol L-1 (molar)
m: Multiple lines MHz: Megahertz min: Minute ml: Milliliter μM: Micromol mol: Mol mmol: mmol MW: Microwave m / z: Mass-to-charge ratio q: Quartet RT: Retention time (HPLC)
rt: room temperature s: singlet t: triplet

Since the compound of the present invention can contain two or more basic amine functional groups, the salt form of the compound of the present invention can contain two or more acid adducts (eg, HCl). For example, for HCl as an acid adduct, the stoichiometry of hydrochloride is variable and may depend on the pKa and HCl equivalents of the compounds used for salt formation. Therefore, the hydrochloride form is x. Expressed as HCl, where x is greater than or equal to 1.

Reagents and solvents were obtained from commercial sources and used without further purification.
Flash chromatographic purification was performed on Merck silica gel (40-63 μM) as the stationary phase.

Analytical Procedure Reagents and solvents were obtained from commercial sources and used without further purification.
Flash chromatographic purification was performed on Merck silica gel (40-63 μM) as the stationary phase.
The structure of the compound of the present invention was confirmed using one or more of the following analytical methods.

NMR method:
Methods 1: ¹ H and ¹³ C NMR were performed using a BRUKER spectrometer Avance III nanobay-300 MHz.
Method 2: ¹ H and ¹³ C NMR were performed using a BRUKER spectrometer Avance III nanobay-300 MHz.

Infrared method:
Infrared spectra were recorded using an IRAFFINITY-1 Fourier Transform Infrared Spectrophotometer (SHIMADZU).

分析実行時間：８分 HPLC / MS / UV Method Method 1: HPLC / MS / UV / MS was performed primarily by the gradient method described below using the AGILENT 1260 Infinity series and the Mass quadrupole Agilent 6120 device.
Flow rate: 2 ml / min Temperature: 35 ° C
Column: Poroshell 120 SB-C18 2.7 μm 4.6 × 75 mm
Mobile phase A: 0.1% formic acid aqueous solution (v / v)
Mobile phase B: Methanol gradient elution:

Analysis execution time: 8 minutes

分析実行時間：２．６分 Method 2: HPLC / UV / MS was performed primarily by the gradient method described below using the AGILENT 1290 series and Mass 6130 quadrupole device.
Flow rate: 0.8 ml / min Temperature: 60 ° C
Column: Acquity UPLCBEH C18 1.7 μm 2.1 × 50 mm
Mobile phase A: 0.1% formic acid aqueous solution (v / v)
Mobile phase B: Formic acid 0.1% acetonitrile Gradient elution:

Analysis execution time: 2.6 minutes

分析実行時間：１６分 Method 3: HPLC / UV was performed mainly by the following gradient method using a Waters Alliance 2695 series device.
Flow rate: 1 ml / min Temperature: Room temperature Column: X-bridge C18 3.5 μm 4.6 × 150 mm
Mobile phase A: 10 mM ammonium acetate in water Mobile phase B: acetonitrile Gradient elution:

Analysis execution time: 16 minutes

分析実行時間：３．２分 Method 4: HPLC / UV / MS was performed primarily using the AGILENT 1290 series and Mass Agilent 6130 quadrupole devices with the following gradient method:
Flow rate: 0.5 ml / min Temperature: 45 ° C
Column: Acquity UPLC BEH C18 1.7 μm 2.1 × 50 mm
Mobile phase A: 0.1% formic acid aqueous solution (v / v)
Mobile phase B: Formic acid 0.1% acetonitrile Gradient elution:

Analysis execution time: 3.2 minutes

分析実行時間：５分 Method 5: HPLC / UV / MS was performed primarily by the gradient method described below using the Waters Alliance 2695 series and the Mass Agilent 6130 quadrupole device.
Flow rate: 2 ml / min Temperature: Room temperature Column: X-bridge C18 3.5 μm 4.6 × 75 mm
Mobile phase A: 10 mM ammonium acetate in water Mobile phase B: acetonitrile Gradient elution:

Analysis execution time: 5 minutes

分析実行時間：３分 Method 6: HPLC / UV / MS was performed primarily by the gradient method described below using the Waters Alliance 2695 series and the Mass Agilent 6130 quadrupole device.
Flow rate: 0.8 ml / min Temperature: 60 ° C
Column: Acquity UPLC BEH C18 1.7 μm 2.1 × 50 mm
Mobile phase A: 0.1% formic acid aqueous solution (v / v)
Mobile phase B: Formic acid 0.1% acetonitrile Gradient elution:

Analysis execution time: 3 minutes

分析実行時間：２．６分 Method 7: HPLC / UV / MS was performed primarily by the gradient method described below using the AGILENT 1200 series and the Mass Agilent 6130 quadrupole device.
Flow rate: 0.8 ml / min Temperature: 60 ° C
Column: Acquity UPLC BEH C18 1.7 μm 2.1 × 50 mm
Mobile phase A: 0.1% formic acid aqueous solution (v / v)
Mobile phase B: Formic acid 0.1% acetonitrile Gradient elution:

Analysis execution time: 2.6 minutes

分析実行時間：４．５分 Method 8: HPLC / UV / MS was performed primarily by the gradient method described below using the AGILENT 1290 series and the Mass Agilent 6130 quadrupole device.
Flow rate: 0.6 ml / min Temperature: 35 ° C
Column: Acquity UPLC BEH C18 1.7 μm 2.1 × 50 mm
Mobile phase A: 0.05% aqueous solution of formic acid (v / v)
Mobile phase B: Formic acid 0.05% acetonitrile Gradient elution:

Analysis execution time: 4.5 minutes

Compounds of formulas I, II, III, IV, starting materials, reactants (eg, alkylating agents (Ig)), and intermediates are well known in the field of chemistry, especially from the point of view of the description herein. And Comprehensive Heterocyclic Chemistry II, Editors Katritzky and Rees, Elsevier, 1997, eg Volume 3; Liebigs Annalen der Chemie, (9): 1910-16, (1985); Helvetica Chimica Acta, 41: 1052- 60, (1958); Arzneimittel-Forschung, 40 (12): 1328-31, (1990) (each of which is expressly incorporated herein by reference) and methods for other heterocycles. It can be synthesized by a synthetic route including a similar method. Starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, WI) or are readily prepared using methods known to those of skill in the art (eg, Louis F. Fieser and Mary). Fieser, Reagents for Organic Synthesis, v. 1-23, Wiley, NY (1967-2006 ed.), Or Beilsteins Handbuch der organischen Chemie, 4, Aufl. Ed. Springer- Verlag, Berlin, including Addendum (Beilstein Online Also available via database) including).
Synthetic chemical conversion and protecting groups (protection and deprotection) useful for the synthesis of compounds of formula I (or II, III, IV) and the required reagents and intermediates are known in the art and are described, for example, in R. Larock. , Comprehensive Organic Transformations, VCH Publishers (1989); TW Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3r Ed., John Wiley and Sons (1999); and L. Paquette, ed., Encyclopedia of Some have been described in Reagents for Organic Synthesis, John Wiley and Sons (1995), and later editions.

Examples provide exemplary methods for preparing compounds of formula I (and II, III, IV). Those skilled in the art will appreciate that compounds of formulas I and II can be synthesized using other synthetic routes. Specific starting materials and reagents are shown and discussed in the figures and examples, but other starting materials and reagents are readily substituted to provide various derivatives and / or reaction conditions. In addition, many of the exemplary compounds prepared by the described methods can be further modified in light of the present disclosure using conventional chemistry known to those of skill in the art.

無水ＴＨＦ（２０ｍｌ）（トルエンとジオキサンを同様に使用することができる）中の２，４−ジクロロキノリン（１０ｍｍｏｌ）の窒素ガス下の溶液に、アミン誘導体（２０ｍｍｏｌ、２当量）とｔ−ＢｕＯＮａ（２８ｍｍｏｌ、２．８当量）を加えた。得られた混合液をアルゴンで１０分間脱気した後、キサントホス、又はアミノアリール−ハロゲンもしくはアミノヘテロアリール−ハロゲンＰｄ補助カップリング反応で通常使用される他の二座ホスフィンリガンド（１０ｍｍｏｌ、０．１当量）及びＰｄ（ＯＡｃ）_２（５．０ｍｍｏｌ、０．０５当量）（使用した二座ホスフィンリガンドに関しては０．５当量の ”Ｐｄ”を使用した、他のＰｄ^（ＩＩ）源を使用することができるが、優先的にはＰｄ（ＯＡｃ）_２）を加え、反応の完了まで反応混合液を加熱還流した。次に、反応混合物を室温に冷却し、減圧下で濃縮した。残留物を食塩水とＡｃＯＥｔに分配し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＭｇＳＯ_４で乾燥し、濾過し、減圧下で濃縮して粗混合物を得た。粗生成物をフラッシュクロマトグラフィーにより精製して、２−（置換アミノ）−４−クロロキノリンを得た。
アミノ置換基は同様にして組み立てることができ、特にＲ^１−Ｗサブ構造は、パラジウム補助アリール／アリールカップリング又はパラジウム補助アリール／アミノアリールカップリングを使用して組み立てることができる。 General Procedure for Palladium Coupling Auxiliary Amine Substitution to 2,4-Dichloroquinoline for the Synthesis of 2- (Substitution-Amino) -4-Chloroquinoline Derivatives

An amine derivative (20 mmol, 2 eq) and t-BuONa (20 mmol, 2 eq) in a solution of 2,4-dichloroquinoline (10 mmol) in anhydrous THF (20 ml) (toluene and dioxane can be used similarly) under nitrogen gas. 28 mmol (2.8 eq) was added. The resulting mixture is degassed with argon for 10 minutes and then xantphos, or other bidentate phosphin ligands (10 mmol, 0.1) commonly used in aminoaryl-halogen or aminoheteroaryl-halogen Pd-auxiliary coupling reactions. Equivalents) and Pd (OAc) ₂ (5.0 mmol, 0.05 equivalents) (for the bidentate phosphine ligands used, 0.5 equivalents of "Pd" were used, using other Pd ^(II) sources. However, Pd (OAc) ₂ ) was preferentially added, and the reaction mixture was heated and refluxed until the reaction was completed. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was partitioned into saline and AcOEt, and the aqueous layer was extracted with AcOEt. The combined organic layers were dried over MgSO _4, filtered to give the crude mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography to give 2- (substituted amino) -4-chloroquinoline.
Amino substituents can be assembled in the same manner, in particular R ¹ -W substructure can be assembled using palladium auxiliary aryl / aryl coupling or palladium auxiliary aryl / aminoaryl coupling.

無水ＴＨＦ（２００ｍｌ）中の２，４−ジクロロキノリン（２０．０ｇ、１０１ｍｍｏｌ）の窒素ガス下の溶液に、４−クロロベンジルアミン（２４．７ｍｌ、２０２ｍｍｏｌ、２当量）及びｔ−ＢｕＯＮａ（２７．２ｇ、２８３ｍｍｏｌ、２．８当量）を加えた。得られた混合液を窒素で１０分間脱気し、次にキサントホス（５．８ｇ、１０．１ｍｍｏｌ、０．１当量）及びＰｄ（ＯＡｃ）_２（１．１ｇ、５．０ｍｍｏｌ、０．０５当量）を加え、反応混合液を３時間加熱還流した。次に反応混合液を室温に冷却し、減圧下で濃縮した。残留物を食塩水とＡｃＯＥｔに分配し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＭｇＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、褐色油状物を得た。粗生成物をフラッシュクロマトグラフィー（勾配 石油エーテル／ＤＣＭ、５／５〜０／１０）により精製して、２−（４−クロロベンジルアミノ）−４−クロロキノリンに対応する１３．５ｇ（収率４４％）の褐色固体を得た。
質量：(ES+) C₁₈H₁₂Cl₂N₂, 計算値 303; 実測値 303-305 [M+H], HPLC/MS 方法１。 Scaffold 2- (4-chlorobenzylamino) -4-chloroquinoline synthesis

In a solution of 2,4-dichloroquinoline (20.0 g, 101 mmol) in anhydrous THF (200 ml) under nitrogen gas, 4-chlorobenzylamine (24.7 ml, 202 mmol, 2 eq) and t-BuONa (27. 2 g, 283 mmol, 2.8 eq) was added. The resulting mixture was degassed with nitrogen for 10 minutes, then xantphos (5.8 g, 10.1 mmol, 0.1 eq) and Pd (OAc) ₂ (1.1 g, 5.0 mmol, 0.05 eq). ) Was added, and the reaction mixture was heated under reflux for 3 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was partitioned into saline and AcOEt, and the aqueous layer was extracted with AcOEt. The combined organic layers were dried over MgSO _4, filtered, and concentrated under reduced pressure to give a brown oil. The crude product was purified by flash chromatography (gradient petroleum ether / DCM, 5/5 to 0/10) to 13.5 g (yield) corresponding to 2- (4-chlorobenzylamino) -4-chloroquinoline. 44%) brown solids were obtained.
Mass: (ES +) C ₁₈ H ₁₂ Cl ₂ N ₂ , Calculated 303; Measured 303-305 [M + H], HPLC / MS Method 1.

２ｍｌのＮＭＰ中の２−（４−クロロベンジルアミノ）−４−クロロキノリン（３００ｍｇ、０．９９ｍｍｏｌ）及び対応する置換２級シクロアミン（１．２５当量）の溶液に、Ｎ，Ｎ−ジイソプロピルエチルアミン（ＤｉＰＥＡ）を加え、得られた混合液を１４０℃で２４時間加熱した。次に反応混合液を冷却し、１Ｎ ＮａＯＨ水溶液（２５ｍｌ）で希釈し、得られた混合液をＡｃＯＥｔで抽出した。合わせた有機層をＭｇＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、褐色油状物を得た。粗生成物をフラッシュクロマトグラフィーで精製した。
次に、化合物をＤＣＭ中で希釈し、Ｅｔ_２Ｏ中の２Ｎ ＨＣｌ溶液（４当量）の添加により、塩酸塩に変換した。得られた溶液を室温で１５分間撹拌し、次に減圧下で濃縮した。得られた塩酸塩をＨ_２Ｏに溶解し、凍結乾燥した。

Synthesis A: General synthesis of 4- (substituted secondary cycloamine) -2- (4-chlorobenzylamino) -quinoline hydrochloride compounds of formula (I) where ^{R 3a} and R ^{3c are equal to H (see Table 5 below).} )

To a solution of 2- (4-chlorobenzylamino) -4-chloroquinoline (300 mg, 0.99 mmol) and the corresponding substituted secondary cycloamine (1.25 eq) in 2 ml of NMP, N, N-diisopropylethylamine ( DiPEA) was added, and the obtained mixed solution was heated at 140 ° C. for 24 hours. Next, the reaction mixture was cooled, diluted with 1N NaOH aqueous solution (25 ml), and the obtained mixture was extracted with AcOEt. The combined organic layers were dried over MgSO _4, filtered, and concentrated under reduced pressure to give a brown oil. The crude product was purified by flash chromatography.
Next, the compound was diluted in DCM, by the addition of 2N HCl solution in Et ₂ O (4 equiv), which was converted into the hydrochloride. The resulting solution was stirred at room temperature for 15 minutes and then concentrated under reduced pressure. The resulting hydrochloride was dissolved in H _{2 O,} and lyophilized.

Chemical structure of the compound prepared according to the above general procedure A:
2- (4-Chlorobenzylamino) -4- [3- (pyrrolidin-1-yl) azetidine-1-yl] quinoline hydrochloride (116), 2- (4-chlorobenzylamino) -4- [3- (Morholin-4-yl) Azetidine-1-yl] quinoline hydrochloride (118), 2- (4-chlorobenzylamino) -4- [4- (methylcarbamoyl) piperidin-1-yl] quinoline hydrochloride (1598) ), 2- (4-Chlorobenzylamino) -4- [4- (tert-butylaminocarbonyl) -piperidin-1-yl] -quinoline hydrochloride (1604), 2- (4-chlorobenzylamino) -4 -[4- (Pyrrolidine-1-carbonyl) piperidin-1-yl] quinoline hydrochloride (1648), 2- (4-chlorobenzylamino) -4- [4- (4-methylpiperazin-1-carbonyl)- Piperidine-1-yl] -quinoline hydrochloride (1656), (2S) 2- (4-chlorobenzylamino) -4- [2- (hydroxymethyl) pyrrolidine-1-yl] quinoline hydrochloride (2308), ( 2S) 2- (4-chlorobenzylamino) -4-[(2- (methoxymethyl) pyrrolidine-1-yl] quinoline hydrochloride (2310), (2R) -2- (4-chlorobenzylamino) -4 -[2- (Hydroxymethyl) -pyrrolidin-1-yl] quinoline hydrochloride (2380), 2- (4-chlorobenzylamino) -4- (4-hydroxypiperidine-1-yl) quinoline hydrochloride (2916) , 2- (4-Chlorobenzylamino) -4- [4- (iso-propoxy) -piperidin-1-yl] -quinoline hydrochloride (2918), 2- (4-chlorobenzylamino) -4- (4) -Phenoxypiperidin-1-yl) -quinoline hydrochloride (2940):

Chemical structure of the compound prepared according to the above general procedure A:
2- (4-Chlorobenzylamino) -4- [4- (m-tolyloxy) piperidin-1-yl] quinoline hydrochloride (2946), 2- (4-chlorobenzylamino) -4- [4- (pyridine) -4-Iloxy) piperidin-1-yl] quinoline hydrochloride (2950), 2- (4-chlorobenzylamino) -4- [4- (pyrazine-2-yloxy) piperidin-1-yl] quinoline hydrochloride ( 2958), (3R) 2- (4-chlorobenzylamino) -4- (3-hydroxypyrrolidin-1-yl) quinoline hydrochloride (2988), (3R) 2- (4-chlorobenzylamino) -4- [3- (Phenoxy) pyrrolidine-1-yl] quinoline hydrochloride (3012), (3R) 2- (4-chlorobenzylamino) -4- [3- (pyridin-2-yloxy) pyrrolidine-1-yl] Kinolin hydrochloride (3026), (3S) 2- (4-chlorobenzylamino) -4- (3-hydroxypyrrolidin-1-yl) -quinoline hydrochloride (3060), (3S) 2- (4-chlorobenzyl) Amino) -4- [3- (pyridin-2-yloxy) pyrrolidine-1-yl] quinoline hydrochloride (3098):

２ｍｌのＮＭＰ中の２−（置換、非置換アリール−ヘテロアリールアミン）−４−クロロキノリン（１ｍｍｏｌ、１．０当量）及び対応する置換２級シクロアミン（１．２５ｍｍｏｌ、１．２５当量）の溶液に、Ｎ，Ｎ−ジイソプロピルエチルアミン（ＤｉＰＥＡ、２〜６当量）を加え、得られた混合液を、反応が完了するまで１４０℃で加熱した（基質反応性に依存して、反応温度は、１２０℃〜２００℃の間で又はマイクロ波オーブン有り又は無しで調整することができる）。次に、反応混合液を冷却し、１Ｎ ＮａＯＨ水溶液（２５ｍｌ）で希釈し、得られた混合液をＡｃＯＥｔで抽出した。合わせた有機層をＭｇＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、褐色油状物を得た。粗生成物をフラッシュクロマトグラフィーで精製した。
次に、化合物をＤＣＭ中で希釈し、Ｅｔ_２Ｏ中の２Ｎ ＨＣｌ溶液（４当量）の添加により塩酸塩に変換した。得られた溶液を室温で１５分間撹拌し、次に減圧下で濃縮した。得られた塩酸塩をＨ_２Ｏに溶解し、最後に凍結乾燥した。 General procedure for the synthesis of 4- (substituted secondary cycloamine) -2- (substituted, unsubstituted aryl-heteroarylamine) -quinoline hydrochloride compounds of formula (I):

A solution of 2- (substituted, unsubstituted aryl-heteroarylamine) -4-chloroquinoline (1 mmol, 1.0 eq) and the corresponding substituted secondary cycloamine (1.25 mmol, 1.25 eq) in 2 ml of NMP. N, N-diisopropylethylamine (DiPEA, 2-6 eq) was added to the mixture, and the resulting mixture was heated at 140 ° C. until the reaction was completed (depending on the substrate reactivity, the reaction temperature was 120). Can be adjusted between ° C and 200 ° C or with or without a microwave oven). Next, the reaction mixture was cooled, diluted with 1N NaOH aqueous solution (25 ml), and the obtained mixture was extracted with AcOEt. The combined organic layers were dried over MgSO _4, filtered, and concentrated under reduced pressure to give a brown oil. The crude product was purified by flash chromatography.
Next, the compound was diluted in DCM, and converted to the hydrochloride salt by addition of 2N HCl solution in Et ₂ O (4 equiv). The resulting solution was stirred at room temperature for 15 minutes and then concentrated under reduced pressure. The resulting hydrochloride was dissolved in H _{2 O,} and finally lyophilized.

Preparation of compound 212: 2- (N-4-chlorobenzyl-N-methylamino) -4- [4- (tert-butylamino) -piperidine-1-yl] -quinoline hydrochloride:

無水ＴＨＦ（１０ｍｌ）中の２，４−ジクロロキノリン（１．００ｇ、５．０ｍｍｏｌ）の窒素ガス下の溶液に、４−クロロ−Ｎ−メチルベンジルアミン（１．５７ｇ、１０．１ｍｍｏｌ、２当量）及びｔ−ＢｕＯＮａ（１．３６ｇ、１４．１ｍｍｏｌ、２．８当量）を加えた。得られた混合液を窒素で５分間脱気し、次にキサントホス（２９２ｍｇ、０．５１ｍｍｏｌ、０．１当量）及びＰｄ（ＯＡｃ）_２（５７ｍｇ、０．２５ｍｍｏｌ）を加え、反応混合液を３時間加熱還流した。次に、反応混合液を室温に冷却し、減圧下で濃縮した。残留物を食塩水とＡｃＯＥｔに分配し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＭｇＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、褐色油状物を得た。粗生成物をフラッシュクロマトグラフィー（勾配、石油エーテル／ＤＣＭ、５／５〜０／１０）により精製して、２−（４−クロロ−Ｎ−メチルベンジルアミノ）−４−クロロキノリンに対応する褐色固体８００ｍｇ（収率５０％を得た。
質量：(ES+) C₁₇H₁₄Cl₂N₂, 計算値 317; 実測値 317-319 [M+H], HPLC/MS 方法１。 Synthesis of 2- (4-chloro-N-methylbenzylamino) -4-chloroquinoline, intermediate 212-I-1

4-Chloro-N-methylbenzylamine (1.57 g, 10.1 mmol, 2 equivalents) in a solution of 2,4-dichloroquinoline (1.00 g, 5.0 mmol) under nitrogen gas in anhydrous THF (10 ml). ) And t-BuONa (1.36 g, 14.1 mmol, 2.8 eq) were added. The obtained mixture was degassed with nitrogen for 5 minutes, then xantphos (292 mg, 0.51 mmol, 0.1 eq) and Pd (OAc) ₂ (57 mg, 0.25 mmol) were added, and the reaction mixture was added to 3 The mixture was heated under reflux for hours. Next, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned into saline and AcOEt, and the aqueous layer was extracted with AcOEt. The combined organic layers were dried over MgSO _4, filtered, and concentrated under reduced pressure to give a brown oil. The crude product is purified by flash chromatography (gradient, petroleum ether / DCM, 5/5 to 0/10) and brown corresponding to 2- (4-chloro-N-methylbenzylamino) -4-chloroquinoline. 800 mg of solid (50% yield) was obtained.
Mass: (ES +) C ₁₇ H ₁₄ Cl ₂ N ₂ , Calculated value 317; Measured value 317-319 [M + H], HPLC / MS Method 1.

２ｍｌのＮＭＰ中の２−（４−クロロ−Ｎ−メチルベンジルアミノ）−４−クロロキノリン（２００ｍｇ、０．６３ｍｍｏｌ）及び４−（ｔｅｒｔ−ブチルアミノ）−ピペリジン（１２３ｍｇ、０．７９ｍｍｏｌ、１．２５当量）の溶液に、Ｎ，Ｎ−ジイソプロピルエチルアミン（１７５μｌ、１．０ｍｍｏｌ）を加え、得られた混合液を１４０℃で４２時間加熱した。次に、反応混合液を冷却し、１Ｎ ＮａＯＨ水溶液（２５ｍｌ）で希釈し、得られた混合液をＡｃＯＥｔで抽出した。合わせた有機層をＭｇＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、黄色油状物を得た。粗生成物をフラッシュクロマトグラフィー（勾配、ＤＣＭ／ＭｅＯＨ、１０／０〜８／２）により精製した。化合物をＤＣＭ中で希釈し、Ｅｔ_２Ｏ中の２Ｎ ＨＣｌ溶液を添加することにより、塩酸塩に変換した。溶液を室温で１５分間撹拌し、次に減圧下で濃縮した。得られた塩酸塩をＨ_２Ｏに溶解した後、凍結乾燥して、２−（Ｎ−４−クロロベンジル−Ｎ−メチルアミノ）−４−［４−（ｔｅｒｔ−ブチルアミノ）−ピペリジン−１−イル］−キノリン塩酸塩に対応する１９４ｍｇ（収率６５％）の白色の固体を得た。 Compound 212: Synthesis of 2- (N-4-chlorobenzyl-N-methylamino) -4- [4- (tert-butylamino) -piperidine-1-yl] -quinoline hydrochloride

2- (4-Chloro-N-methylbenzylamino) -4-chloroquinoline (200 mg, 0.63 mmol) and 4- (tert-butylamino) -piperidine (123 mg, 0.79 mmol) in 2 ml of NMP, 1. N, N-diisopropylethylamine (175 μl, 1.0 mmol) was added to the solution (25 eq), and the resulting mixture was heated at 140 ° C. for 42 hours. Next, the reaction mixture was cooled, diluted with 1N NaOH aqueous solution (25 ml), and the obtained mixture was extracted with AcOEt. The combined organic layers were dried over MgSO _4, filtered, and concentrated under reduced pressure to give a yellow oil. The crude product was purified by flash chromatography (gradient, DCM / MeOH / 10 / 0-8 / 2). Compounds were diluted in DCM, by addition of 2N HCl solution in Et ₂ O, it was converted to the hydrochloride salt. The solution was stirred at room temperature for 15 minutes and then concentrated under reduced pressure. The obtained hydrochloride _{is dissolved in H 2} O, dried by freezing and drying, and 2- (N-4-chlorobenzyl-N-methylamino) -4- [4- (tert-butylamino) -piperidine-1. -Il] -A white solid of 194 mg (65% yield) corresponding to quinoline hydrochloride was obtained.

アセトニトリル（３ｍｌ）中の２−（４−クロロベンジルアミノ）−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）−キノリン（１００ｍｇ、０．２４ｍｍｏｌ）の溶液に、ハロゲン化アルキル（４当量）及びＮａＨ（油中６０％、４当量）を加えた。得られた混合液を２４時間加熱還流した。次に、反応混合液を室温に冷却し、冷水（１０ｍｌ）で希釈し、得られた混合液をＡｃＯＥｔで抽出した。合わせた有機層をＭｇＳＯ_４で乾燥し、濾過し、減圧下で濃縮した。粗生成物をフラッシュクロマトグラフィーで精製した。

Synthetic B: General 2- (N-4-chlorobenzyl-N-alkylamino) -4- [4- (tert-butylamino) -piperidine-1-yl] -quinoline derivative (214,216, 220) Synthesis:

A solution of 2- (4-chlorobenzylamino) -4- (4-tert-butylaminopiperidin-1-yl) -quinoline (100 mg, 0.24 mmol) in acetonitrile (3 ml) with an alkyl halide (4 eq). ) And NaH (60% in oil, 4 equivalents). The obtained mixed solution was heated under reflux for 24 hours. Next, the reaction mixture was cooled to room temperature, diluted with cold water (10 ml), and the obtained mixture was extracted with AcOEt. The combined organic layers were dried over MgSO _4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography.

Compounds were diluted in DCM, by adding a solution of in Et ₂ O in 2N HCl (4 eq) was converted to the hydrochloride salt. The solution was stirred at room temperature for 15 minutes and then concentrated under reduced pressure. Next, the obtained hydrochloride was dissolved in H _{2 O,} and lyophilized.

Chemical structure of compounds prepared according to General Procedure B above:
2- (N-4-chlorobenzyl-N-ethylamino) -4- [4- (tert-butylamino) -piperidin-1-yl] -quinoline hydrochloride (214), 2- (N-4-chloro) Benzyl-N-isopropylamino) -4- [4- (tert-butylamino) -piperidin-1-yl] -quinoline hydrochloride (216), 2- (N-4-chlorobenzyl-N-isobutylamino)- 4- [4- (tert-butylamino) -piperidin-1-yl] -quinoline (220).

アセトニトリル（３〜１０ｍｌ）中のモノ置換２−アミノキノリン誘導体Ａ−１（１ｍｍｏｌ）の０℃溶液に、アルキル化ハロゲン化物（４当量）及びＮａＨ（油中６０％、４当量）を加えた。得られた混合液を室温まで加熱し、又は基質反応性に依存して、反応混合液を反応完了まで、室温から１２０℃で加熱することができる（溶媒としてＭｅＣＮ、ＴＨＦ、ＭＴＨＦ、又はＤＭＦを使用）。反応中に臭化テトラブチルアンモニウム、ヨウ化テトラブチルアンモニウム、臭化ベンジルトリエチルアンモニウム、塩化ベンジルトリエチルアンモニウムなどの触媒量の四級ハロゲン化アンモニウムの触媒量を使用することができ、一置換２−アミノキノリン誘導体（Ｉ−ｆ）の反応性に依存して、水素化ナトリウムをＫ_２ＣＯ_３又はＣｓ_２ＣＯ_３（２〜６当量）に置き換えてもよい。炭酸塩塩基を使用する場合、ＭｅＣＮ、ＴＨＦ、ＭＴＨＦ、ＤＭＦ、ＮＭＰ、又はトルエンを溶媒として使用することができる。次に、反応混合液を室温に冷却し、冷水（１０〜５０ｍｌ）で希釈し、得られた混合液をＡｃＯＥｔで抽出した。合わせた有機層をＭｇＳＯ_４で乾燥し、濾過し、減圧下で濃縮した。粗生成物をフラッシュクロマトグラフィーで精製して、式（Ｉ）のＲ^３ｃ置換２−アミノ−キノリン誘導体を得た。 General procedure for synthesizing 2- (N, N-disubstituted amino) -4- [substituted secondary cycloamine) -quinoline derivatives obtained by N-alkylation

Alkylated halides (4 eq) and NaH (60% in oil, 4 eq) were added to a 0 ° C. solution of the mono-substituted 2-aminoquinoline derivative A-1 (1 mmol) in acetonitrile (3-10 ml). The resulting mixture can be heated to room temperature or, depending on the substrate reactivity, the reaction mixture can be heated from room temperature to 120 ° C. until the reaction is complete (MeCN, THF, MTHF, or DMF as the solvent). use). A catalytic amount of quaternary ammonium halide such as tetrabutylammonium bromide, tetrabutylammonium iodide, benzyltriethylammonium bromide, benzyltriethylammonium chloride can be used during the reaction, with mono-substituted 2-amino. Depending on the reactivity of the quinoline derivative (If), sodium hydride _{may be replaced with K 2} CO ₃ or Cs ₂ CO ₃ (2-6 equivalents). When a carbonate base is used, MeCN, THF, MTHF, DMF, NMP, or toluene can be used as a solvent. Next, the reaction mixture was cooled to room temperature, diluted with cold water (10 to 50 ml), and the obtained mixture was extracted with AcOEt. The combined organic layers were dried over MgSO _4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography to give the ^R3c- substituted 2-amino-quinoline derivative of formula (I).

Preparation of Compound 348, 2- (4-Chlorobenzylamino) -3-fluoro-4- [4- (tert-butylamino) piperidine-1-yl] quinoline hydrochloride

ジエチル２−フルオロマロン酸エステル（１．０ｇ、５．６１７ｍｍｏｌ）に、エタノール（１０ｍｌ）、水（１０ｍｌ）、及び水酸化リチウム一水和物（０．９４３ｇ、２２．４７ｍｍｏｌ）を加え、次に反応物を５０℃で１６時間よく攪拌した。次に、反応混合液を室温に冷却し、減圧下で濃縮した。残留物をＭＴＢＥ及び水で希釈し、次に混合液を６Ｎ ＨＣｌで酸性化し、次にＭＴＢＥ（５×５０ｍｌ）で抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して２−フルオロマロン酸に対応する４００ｍｇ（収率５８％）の白色固体を得た。粗生成物をさらに精製することなく次の工程で使用した。 Synthesis of 2-fluoromalonic acid, intermediate 348-I-1

To diethyl 2-fluoromalonic acid ester (1.0 g, 5.617 mmol), ethanol (10 ml), water (10 ml), and lithium hydroxide monohydrate (0.943 g, 22.47 mmol) are added, and then The reaction was stirred well at 50 ° C. for 16 hours. Next, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with MTBE and water, then the mixture was acidified with 6N HCl and then extracted with MTBE (5 x 50 ml). The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give 400 mg (58% yield) of white solid corresponding to 2-fluoromalonic acid. The crude product was used in the next step without further purification.

化合物３４８−Ｉ−１（１．０ｇ、８．１９６ｍｍｏｌ）に塩化ホスホリル（２０ｍｌ）を加え、次に反応物を８０℃で３０分間よく攪拌し、次に反応混合液を５０℃に冷却した。粗混合液にアニリン（０．６０９ｇ、６．５５７ｍｍｏｌ）を少しずつ加え、得られた混合液を８０℃で１６時間撹拌した。反応混合液を室温にし、氷水に注ぎ、次にアンモニア水溶液でクエンチし、次に水層をＡｃＯＥｔ（２×５０ｍｌ）で抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して粗化合物を得て、これをフラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＡｃＯＥｔ−石油エーテル；２：９８→５：９５）により精製して、２，４−ジクロロ−３−フルオロキノリンに対応する４００ｍｇ（収率２３％）の白色固体を得た。
質量：(ES+) C₉H₄Cl₂FN 計算値 214.97; 実測値 215.9 [M+H], HPLC/MS 方法７。 Synthesis of 2,4-dichloro-3-fluoroquinoline, intermediate 348-I-2

Phosphoryl chloride (20 ml) was added to compound 348-I-1 (1.0 g, 8.196 mmol), then the reaction was stirred well at 80 ° C. for 30 minutes and then the reaction mixture was cooled to 50 ° C. Aniline (0.609 g, 6.557 mmol) was added little by little to the crude mixed solution, and the obtained mixed solution was stirred at 80 ° C. for 16 hours. The reaction mixture was brought to room temperature, poured into ice water, then quenched with aqueous ammonia, and then the aqueous layer was extracted with AcOEt (2 x 50 ml). The combined organic layer was _{dried with Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a crude compound, which was subjected to flash chromatography (silica gel: 100-200 mesh, AcOEt-petroleum ether; 2:98 → Purification according to 5:95) gave 400 mg (23% yield) of white solid corresponding to 2,4-dichloro-3-fluoroquinoline.
Mass: (ES +) C ₉ H ₄ Cl ₂ FN Calculated 214.97; Measured 215.9 [M + H], HPLC / MS Method 7.

ＴＨＦ（２０ｍｌ）中の化合物３４８−Ｉ−２（０．４ｇ、１．８６０ｍｍｏｌ）の窒素下の溶液に、４−クロロベンジルアミン（０．３９５ｇ、２．７９１ｍｍｏｌ）及びｔ−ＢｕＯＮａ（０．５４１ｇ、５．５８２ｍｍｏｌ）を加えた。得られた混合液をＡｒガスで３０分間脱気し、次にキサントホス（１０８ｍｇ、０．１８６０ｍｍｏｌ）及び酢酸パラジウム（４２ｍｇ、０．１８６０ｍｍｏｌ）を加え、反応混合液を８０℃で３時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、減圧下で濃縮した。残留物を食塩水とＡｃＯＥｔに分配し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して褐色油状物を得た。粗化合物を、フラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＡｃＯＥｔ−石油エーテル；１０：９０→５０：５０）により精製して、２−（４−クロロベンジルアミノ）−３−フルオロ−４−クロロキノリンに対応する３００ｍｇ（収率５０％）の白色固体を得た。（化合物３４８−Ｉ−３は、ＨＭＢＣ ＮＭＲ実験により確認された）。
質量：(ES+) C₁₆H₁₁Cl₂FN₂ 計算値 320.03; 実測値 321.22 [M+H], HPLC/MS 方法４。 Synthesis of 2- (4-chlorobenzylamino) -3-fluoro-4-chloroquinoline, intermediate 348-I-3

4-Chlorobenzylamine (0.395 g, 2.791 mmol) and t-BuONa (0.541 g) in a solution of compound 348-I-2 (0.4 g, 1.860 mmol) in THF (20 ml) under nitrogen. 5.582 mmol) was added. The obtained mixture was degassed with Ar gas for 30 minutes, then xantphos (108 mg, 0.1860 mmol) and palladium acetate (42 mg, 0.1860 mmol) were added, and the reaction mixture was stirred at 80 ° C. for 3 hours. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned into saline and AcOEt, and the aqueous layer was extracted with AcOEt. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown oil. The crude compound is purified by flash chromatography (silica gel: 100-200 mesh, AcOEt-petroleum ether; 10:90 → 50:50) and 2- (4-chlorobenzylamino) -3-fluoro-4-chloro. A 300 mg (50% yield) white solid corresponding to quinoline was obtained. (Compound 348-I-3 was confirmed by HMBC NMR experiment).
Mass: (ES +) C ₁₆ H ₁₁ Cl ₂ FN ₂ Calculated 320.03; Measured 321.22 [M + H], HPLC / MS Method 4.

６ｍｌのＮＭＰ中の化合物３４８−Ｉ−３（３００ｍｇ、０．９３６ｍｍｏｌ）の溶液に、４−（ｔｅｒｔ−ブチルアミノ）−ピペリジン（５８０ｍｇ、３．７５ｍｍｏｌ）を加え、混合液をマイクロ波オーブン中で１４０℃で３時間加熱した。次に、反応混合液を氷水で冷却、希釈し、濾過し、集めた固体をフラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＡｃＯＥｔ−石油エーテル；１０：９０→５０：５０）により精製して、２−（４−クロロベンジルアミノ）−３−フルオロ−４−［４−（ｔｅｒｔ−ブチルアミノ）ピペリジン−１−イル］キノリンに対応する１００ｍｇ（収率２４％）の白色固体を得た。
質量：(ES+) C₂₅H₃₀ClFN₄ 計算値 440.21; 実測値 441.22 [M+H], HPLC/MS 方法２。 Synthesis of the free base of compound 348, 2- (4-chlorobenzylamino) -3-fluoro-4- [4- (tert-butylamino) piperidine-1-yl] quinoline

To a solution of compound 348-I-3 (300 mg, 0.936 mmol) in 6 ml NMP was added 4- (tert-butylamino) -piperidine (580 mg, 3.75 mmol) and the mixture was placed in a microwave oven. It was heated at 140 ° C. for 3 hours. Next, the reaction mixture was cooled with ice water, diluted, filtered, and the collected solid was purified by flash chromatography (silica: 100-200 mesh, AcOEt-petroleum ether; 10:90 → 50:50). A 100 mg (24% yield) white solid corresponding to 2- (4-chlorobenzylamino) -3-fluoro-4- [4- (tert-butylamino) piperidin-1-yl] quinoline was obtained.
Mass: (ES +) C ₂₅ H ₃₀ ClFN ₄ Calculated 440.21; Measured 441.22 [M + H], HPLC / MS Method 2.

２ｍｌの１，４−ジオキサン中の化合物３４８の遊離塩基（０．１ｇ、０．２２７ｍｍｏｌ）の溶液に、１，４−ジオキサン（２．０ｍｌ）中の４Ｍ ＨＣｌを加え、混合液を室温で１時間撹拌した。反応混合液を減圧下で濃縮し、ジエチルエーテルで洗浄して、２−（４−クロロベンジルアミノ）−３−フルオロ−４−［４−（ｔｅｒｔ−ブチルアミノ）ピペリジン−１−イル］キノリン塩酸塩に対応する９５ｍｇ（収率８８％）のオフホワイトの固体を得た。
質量：( ES+) C₂₅H₃₁Cl₂FN₄ 計算値 476.19 ; 実測値 441[M-HCl +H], HPLC/MS 方法２。 Synthesis of compounds 348, 2- (4-chlorobenzylamino) -3-fluoro-4- [4- (tert-butylamino) piperidine-1-yl] quinoline hydrochloride

To a solution of the free base (0.1 g, 0.227 mmol) of compound 348 in 2 ml of 1,4-dioxane, add 4M HCl in 1,4-dioxane (2.0 ml) and mix 1 at room temperature. Stir for hours. The reaction mixture is concentrated under reduced pressure, washed with diethyl ether, and 2- (4-chlorobenzylamino) -3-fluoro-4- [4- (tert-butylamino) piperidine-1-yl] quinoline hydrochloride. A 95 mg (88% yield) off-white solid corresponding to the salt was obtained.
Mass: (ES +) C ₂₅ H ₃₁ Cl ₂ FN ₄ Calculated value 476.19; Measured value 441 [M-HCl + H], HPLC / MS Method 2.

Preparation of Compound 240-F, 2- (4-Fluorobenzylamino) -3-fluoro-4- [4- (tert-butylamino) piperidine-1-yl] quinoline

ＴＨＦ（１０ｍｌ）中の２，４−ジクロロ−３−フルオロキノリン（１．０ｍｍｏｌ）の窒素ガス下の溶液に、４−フルオロベンジルアミン（１．１ｍｍｏｌ）及びＣｓ_２ＣＯ_３（３．０ｍｍｏｌ）を加えた。得られた混合液をＡｒガスで３０分間脱気し、次にキサントホス（０．０５ｍｍｏｌ）及びＰｄ_２（ｄｂａ）_３（０．０５ｍｍｏｌ）を加え、反応混合液を室温で１４時間撹拌した。次に、反応混合液を濾過し、減圧下で濃縮した。残留物を食塩水とＥｔＯＡｃで分配し、水層をＥｔＯＡｃで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、褐色固体を得た。粗化合物をフラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＥｔＯＡｃ−石油エーテル）により精製して、２−（４−フルオロベンジルアミノ）−３−フルオロ−４−クロロキノリンに対応する白色固体を収率５０％で得た。 Synthesis of 2- (4-fluorobenzylamino) -3-fluoro-4-chloroquinoline (348-1--4)

_{4-Fluorobenzylamine (1.1 mmol) and Cs 2} CO ₃ (3.0 mmol) in a solution of 2,4-dichloro-3-fluoroquinoline (1.0 mmol) in THF (10 ml) under nitrogen gas. added. The resulting mixture was degassed with Ar gas for 30 minutes, then xantphos (0.05 mmol) and Pd ₂ (dba) ₃ (0.05 mmol) were added, and the reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was then filtered and concentrated under reduced pressure. The residue was partitioned between saline and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown solid. The crude compound is purified by flash chromatography (silica gel: 100-200 mesh, EtOAc-petroleum ether) to yield a white solid corresponding to 2- (4-fluorobenzylamino) -3-fluoro-4-chloroquinoline. Obtained at 50%.

２−（４−フルオロベンジルアミノ）−３−フルオロ−４−クロロ−キノリン（１．０ｍｍｏｌ）及びＮ−ｔｅｒｔ−ブチルピペリジン−４−アミン（２．０ｍｍｏｌ）を密閉管中に採取し、反応混合液を１８０℃で２４時間攪拌した。次に、反応混合液を室温に冷却し、残留物をメタノールに溶解し、減圧下で濃縮して褐色固体を得た。粗化合物を、フラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＤＣＭ−ＭｅＯＨ；１％〜３％）により精製して、少量の不純物を含む１００ｍｇの白色固体を得た。この物質を分取ＨＰＬＣにより精製して、２−（４−フルオロベンジルアミノ）−３−フルオロ−４−［４−（ｔｅｒｔ−ブチルアミノ）ピペリジン−１−イル］キノリンをオフホワイトの固体として収率１３％で得た。 Synthesis of 2- (4-fluorobenzylamino) -3-fluoro-4- [4- (tert-butylamino) piperidine-1-yl] quinoline (240-F):

2- (4-Fluorobenzylamino) -3-fluoro-4-chloro-quinoline (1.0 mmol) and N-tert-butylpiperidin-4-amine (2.0 mmol) were collected in a closed tube and mixed for reaction. The liquid was stirred at 180 ° C. for 24 hours. The reaction mixture was then cooled to room temperature, the residue was dissolved in methanol and concentrated under reduced pressure to give a brown solid. The crude compound was purified by flash chromatography (silica gel: 100-200 mesh, DCM-MeOH; 1% -3%) to give 100 mg of a white solid containing a small amount of impurities. This material is purified by preparative HPLC to yield 2- (4-fluorobenzylamino) -3-fluoro-4- [4- (tert-butylamino) piperidine-1-yl] quinoline as an off-white solid. Obtained at a rate of 13%.

Preparation of Compound 350, 2- (4-Chlorobenzylamino) -3-methyl-4- [4- (tert-butylamino) piperidine-1-yl] quinoline hydrochloride

１，４−ジオキサン（２ｍｌ）中の２，４−ジクロロ−３−メチルキノリン（０．０５ｇ、０．２３６ｍｍｏｌ）の窒素ガス下の溶液に、４−クロロベンジルアミン（０．０４９ｇ、０．３５ｍｍｏｌ）及び炭酸セシウム（０．１９２ｇ、０．５９ｍｍｏｌ）を加えた。得られた混合液をＡｒガスで３０分間脱気し、次にキサントホス（１３ｍｇ、０．０２３ｍｍｏｌ）及びＰｄ_２（ｄｂａ）_３（２２ｍｇ、０．０２３ｍｍｏｌ）を加え、反応混合液を１００℃で３時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、減圧下で濃縮した。残留物を食塩水とＡｃＯＥｔに分配し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して褐色油状物を得た。粗化合物を、フラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＡｃＯＥｔ−石油エーテル；１０：９０→１５：８５）により精製して、４−クロロ−Ｎ−（４−クロロベンジル）−３−メチルキノリン−２−アミンに対応する３５ｍｇ（収率４７％）の白色固体を得た。
質量：(ES+) C₁₇H₁₄Cl₂N₂ 計算値 316; 実測値 317 [M+H], HPLC/MS 方法２。 Synthesis of 2- (4-chlorobenzylamino) -3-methyl-4-chloroquinoline, intermediate 350-I-1:

4-Chlorobenzylamine (0.049 g, 0.35 mmol) in a solution of 2,4-dichloro-3-methylquinoline (0.05 g, 0.236 mmol) in nitrogen gas in 1,4-dioxane (2 ml). ) And cesium carbonate (0.192 g, 0.59 mmol) were added. The obtained mixed solution was degassed with Ar gas for 30 minutes, then xantphos (13 mg, 0.023 mmol) and Pd ₂ (dba) ₃ (22 mg, 0.023 mmol) were added, and the reaction mixed solution was prepared at 100 ° C. for 3 Stir for hours. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned into saline and AcOEt, and the aqueous layer was extracted with AcOEt. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown oil. The crude compound was purified by flash chromatography (silica gel: 100-200 mesh, AcOEt-petroleum ether; 10:90 → 15:85) to 4-chloro-N- (4-chlorobenzyl) -3-methylquinoline. A 35 mg (47% yield) white solid corresponding to -2-amine was obtained.
Mass: (ES +) C ₁₇ H ₁₄ Cl ₂ N ₂ Calculated value 316; Measured value 317 [M + H], HPLC / MS Method 2.

２ｍｌのＮＭＰ中の２−（４−クロロベンジルアミノ）−３−メチル−４−クロロキノリン ３５０−Ｉ−１（０．３３ｇ、１．０４ｍｍｏｌ）の溶液に、４−（ｔｅｒｔ−ブチルアミノ）−ピペリジン（０．４９ｇ、３．１３ｍｍｏｌ）を加え、混合液をマイクロ波中で２２０℃で２時間加熱した。次に、反応混合液を氷水で冷却、希釈し、濾過し、集めた固体を分取ＨＰＬＣで精製して、２−（４−クロロベンジルアミノ）−３−メチル−４−［４−（ｔｅｒｔ−ブチルアミノ）ピペリジン−１−イル］キノリンに対応する４５ｍｇ（収率１１％）の白色固体を得た。
質量：(ES+) C₂₆H₃₃ClN₄, 計算値 436; 実測値 437 [M +H], HPLC/MS 方法２。 2- (4-Chlorobenzylamino) -3-methyl-4- [4- (tert-butylamino) piperidine-1-yl] quinoline, synthesis of the free base of the compound of Example 350

In a solution of 2- (4-chlorobenzylamino) -3-methyl-4-chloroquinoline 350-I-1 (0.33 g, 1.04 mmol) in 2 ml of NMP, 4- (tert-butylamino)-. Piperidine (0.49 g, 3.13 mmol) was added and the mixture was heated in microwaves at 220 ° C. for 2 hours. The reaction mixture is then cooled with ice water, diluted and filtered, and the collected solid is purified by preparative HPLC to 2- (4-chlorobenzylamino) -3-methyl-4- [4- (tert). A 45 mg (11% yield) white solid corresponding to the −butylamino) piperidine-1-yl] quinoline was obtained.
Mass: (ES +) C ₂₆ H ₃₃ ClN ₄ , Calculated value 436; Measured value 437 [M + H], HPLC / MS Method 2.

１ｍｌのＤＣＭ中の２−（４−クロロベンジルアミノ）−３−メチル−４−［４−（ｔｅｒｔ−ブチルアミノ）ピペリジン−１−イル］キノリン（４５ｍｇ、１０３ｍｍｏｌ）の溶液に、ジエチルエーテル（１．０ｍｌ）中の２Ｍ ＨＣｌを加え、混合液を室温で３０分間撹拌した。反応混合液を減圧下で濃縮し、ジエチルエーテルで洗浄して、２−（４−クロロベンジルアミノ）−３−メチル−４−［４−（ｔｅｒｔ−ブチルアミノ）ピペリジン−１−イル］キノリン塩酸塩に対応する４１ｍｇ（収率７８％）のオフホワイトの固体を得た。
質量：(ES+) C₂₆H₃₄Cl₂N₄ 計算値 436 [M-HCl]; 実測値 437 [M-HCl+H], HPLC/MS 方法２。 Synthesis of Compound of Example 350, 2- (4-chlorobenzylamino) -3-methyl-4- [4- (tert-butylamino) piperidine-1-yl] quinoline hydrochloride

Diethyl ether (1) in a solution of 2- (4-chlorobenzylamino) -3-methyl-4- [4- (tert-butylamino) piperidine-1-yl] quinoline (45 mg, 103 mmol) in 1 ml DCM. 2M HCl in (0.0 ml) was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture is concentrated under reduced pressure, washed with diethyl ether, and 2- (4-chlorobenzylamino) -3-methyl-4- [4- (tert-butylamino) piperidine-1-yl] quinoline hydrochloride. 41 mg (78% yield) of off-white solids corresponding to the salt was obtained.
Mass: (ES +) C ₂₆ H ₃₄ Cl ₂ N ₄ Calculated value 436 [M-HCl]; Measured value 437 [M-HCl + H], HPLC / MS Method 2.

Preparation of Compounds 354,4- (4- (tert-butylamino) piperidine-1-yl) -2- (4-chlorobenzylamino) quinoline-3-carboxylic acid methyl hydrochloride

マロン酸ジメチル（２．９ｍｌ、２２ｍｍｏｌ）を、−１０℃の無水ＤＭＦ（５０ｍｌ）中の鉱油中の６０％水素化ナトリウム（０．８８３ｇ、３６．８ｍｍｏｌ）の懸濁液に、窒素下でゆっくり加えた。室温で３０分間撹拌後、無水イサト酸（３．０ｇ、１８．４ｍｍｏｌ）を加え、反応混合液を１１５℃で３時間加熱した。反応混合液を室温に冷却し、氷水に注ぎ、２Ｍ ＨＣｌで酸性化した。得られた沈殿物を濾過により集めて、粗４−ヒドロキシ−２−オキソ−１，２−ジヒドロキノリン−３−カルボン酸メチルを得て、これをさらに精製することなく次の工程に使用した（収量２．８９ｇ≒約６０％）。 Synthesis of 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate methyl, intermediate 354-I-1

Dimethyl malonate (2.9 ml, 22 mmol) slowly under nitrogen in a suspension of 60% sodium hydride (0.883 g, 36.8 mmol) in mineral oil in anhydrous DMF (50 ml) at -10 ° C. added. After stirring at room temperature for 30 minutes, isatoic anhydride (3.0 g, 18.4 mmol) was added, and the reaction mixture was heated at 115 ° C. for 3 hours. The reaction mixture was cooled to room temperature, poured into ice water and acidified with 2M HCl. The resulting precipitate was collected by filtration to give the crude methyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate, which was used in the next step without further purification (). Yield 2.89 g ≈ 60%).

４−ヒドロキシ−２−オキソ−１，２−ジヒドロキノリン−３−カルボン酸メチル（１．５ｇ、６．８４ｍｍｏｌ）に塩化ホスホリル（２５ｍｌ）を加えた。得られた混合液を８０℃で４時間撹拌した。反応をＴＬＣ（３０％酢酸エチル／石油エーテル）で追跡した。反応の完了後、反応混合液を室温にし、氷水に注ぎ、ＡｃＯＥｔ（２×５０ｍｌ）で抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、粗化合物を得て、これを、フラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＡｃＯＥｔ−石油エーテル；１：９９→１０：９０）により精製して、２，４−ジクロロキノリン−３−カルボン酸メチルに対応する１．０ｇ（収率４７％）のオフホワイトの固体を得た。 Synthesis of 2,4-dichloroquinoline-3-carboxylate methyl, intermediate 354-I-2

Phosphoryl chloride (25 ml) was added to methyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (1.5 g, 6.84 mmol). The obtained mixed solution was stirred at 80 ° C. for 4 hours. The reaction was followed by TLC (30% ethyl acetate / petroleum ether). After completion of the reaction, the reaction mixture was brought to room temperature, poured into ice water, and extracted with AcOEt (2 × 50 ml). The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a crude compound, which was subjected to flash chromatography (silica gel: 100-200 mesh, AcOEt-petroleum ether; 1: Purification by 99 → 10: 90) gave 1.0 g (47% yield) of off-white solids corresponding to methyl 2,4-dichloroquinoline-3-carboxylate.

ＭｅＣＮ（２５ｍｌ）中の２，４−ジクロロキノリン−３−カルボン酸メチル（０．８９ｇ、３．５０ｍｍｏｌ）の撹拌溶液に、室温、フラスコ中で４−ｔｅｒｔ−ブチルアミノピペリジン（０．６７ｇ、４．６４ｍｍｏｌ）を加え、１００℃で１６時間攪拌した。反応をＴＬＣ（３０％酢酸エチル／石油エーテル）で追跡した。反応の完了後、反応混合液を室温にし、氷水に注ぎ、ＡｃＯＥｔ（２×２５ｍｌ）で抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して粗化合物を得て、これをフラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＡｃＯＥｔ−石油エーテル；５：９５→２０：８０）により精製して、４−（４−（ｔｅｒｔ−ブチルアミノ）ピペリジン−１−イル）−２−クロロキノリン−３−カルボン酸メチルに対応する０．５ｇ（収率３８％）のオフホワイトの固体を得た。化合物は、ＮＯＥ ^１Ｈ ＮＭＲ実験により確認した。
質量：(ES+) C₂₀H₂₆ClN₃O₂計算値 375 実測値 376 [M+H], HPLC/MS 方法２。 Synthesis of 4- (4- (tert-butylamino) piperidine-1-yl) -2-chloroquinoline-3-carboxylate methyl, intermediate 354-I-3

In a stirred solution of methyl 2,4-dichloroquinoline-3-carboxylate (0.89 g, 3.50 mmol) in MeCN (25 ml) at room temperature, in a flask 4-tert-butylaminopiperidine (0.67 g, 4). .64 mmol) was added, and the mixture was stirred at 100 ° C. for 16 hours. The reaction was followed by TLC (30% ethyl acetate / petroleum ether). After completion of the reaction, the reaction mixture was brought to room temperature, poured into ice water, and extracted with AcOEt (2 × 25 ml). The combined organic layer was _{dried with Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a crude compound, which was subjected to flash chromatography (silica gel: 100-200 mesh, AcOEt-petroleum ether; 5:95 → Purified by 20:80) in 0.5 g (38% yield) corresponding to methyl 4- (4- (tert-butylamino) piperidine-1-yl) -2-chloroquinoline-3-carboxylate. An off-white solid was obtained. The compounds were ^{confirmed by NOE 1 1} H NMR experiments.
Mass: (ES +) C ₂₀ H ₂₆ ClN ₃ O ₂ Calculated value 375 Measured value 376 [M + H], HPLC / MS Method 2.

トルエン（２０ｍｌ）中の４−（４−（ｔｅｒｔ−ブチルアミノ）ピペリジン−１−イル）−２−クロロキノリン−３−カルボン酸メチル（０．２ｇ、０．５３ｍｍｏｌ）の窒素ガス下の溶液に、４−クロロベンジルアミン（０．１１３ｇ、０．７９９ｍｍｏｌ）及びナトリウムｔｅｒｔ−ブトキシド（０．１２７ｇ、１．３２ｍｍｏｌ）を加えた。得られた混合液をアルゴンガスで３０分間脱気し、次にキサントホス（０．０２８ｍｇ、０．０５ｍｍｏｌ）及びＰｄ_２（ｄｂａ）_３（０．０４８ｍｇ、０．０５ｍｍｏｌ）を加え、反応混合液を１００℃で１時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、減圧下で濃縮した。残留物を食塩水とＡｃＯＥｔに分配し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、褐色油状物を得た。化合物を、フラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＭｅＯＨ−ＤＣＭ ０→１０）により精製して、４−（４−（ｔｅｒｔ−ブチルアミノ）ピペリジン−１−イル）−２−（４−クロロベンジルアミノ）キノリン−３−カルボン酸メチルに対応する０．０４ｇ（収率２８％）の白色固体を得た。 Synthesis of free base of 4- (4- (tert-butylamino) piperidine-1-yl) -2- (4-chlorobenzylamino) quinoline-3-carboxylate methyl, compound of Example 354

In a solution of methyl 4- (4- (tert-butylamino) piperidine-1-yl) -2-chloroquinoline-3-carboxylate (0.2 g, 0.53 mmol) in toluene (20 ml) under nitrogen gas. , 4-Chlorobenzylamine (0.113 g, 0.799 mmol) and sodium tert-butoxide (0.127 g, 1.32 mmol) were added. The obtained mixed solution was degassed with argon gas for 30 minutes, then xantphos (0.028 mg, 0.05 mmol) and Pd ₂ (dba) ₃ (0.048 mg, 0.05 mmol) were added, and the reaction mixed solution was added. The mixture was stirred at 100 ° C. for 1 hour. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned into saline and AcOEt, and the aqueous layer was extracted with AcOEt. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown oil. The compound was purified by flash chromatography (silica gel: 100-200 mesh, MeOH-DCM 0 → 10) and 4- (4- (tert-butylamino) piperidine-1-yl) -2- (4-chloro). A white solid of 0.04 g (yield 28%) corresponding to methyl benzylamino) quinoline-3-carboxylate was obtained.

２ｍｌのジエチルエーテル中のチル４−（４−（ｔｅｒｔ−ブチルアミノ）ピペリジン−１−イル）−２−（４−クロロベンジルアミノ）キノリン−３−カルボン酸メチル（０．０４ｇ、０．０７２ｍｍｏｌ）の溶液に、ジエチルエーテル（２．０ｍｌ）中の２Ｍ ＨＣｌを加え、混合液を室温で３時間撹拌した。反応混合液を減圧下で濃縮し、ジエチルエーテルで洗浄して、４−（４−（ｔｅｒｔ−ブチルアミノ）ピペリジン−１−イル）−２−（４−クロロベンジルアミノ）キノリン−３−カルボン酸メチル塩酸塩に対応する４３ｍｇ（収率９３％）のオフホワイトの固体を得た。
質量：(ES+) C₂₇H₃₄Cl₂N₄O₂ 計算値 480 (M-HCl) 実測値 481 [M+H], HPLC/MS 方法４。 Synthesis of Compounds 354,4- (4- (tert-butylamino) piperidine-1-yl) -2- (4-chlorobenzylamino) quinoline-3-carboxylic acid methyl hydrochloride

Methyl tyl 4- (4- (tert-butylamino) piperidin-1-yl) -2- (4-chlorobenzylamino) quinoline-3-carboxylate (0.04 g, 0.072 mmol) in 2 ml of diethyl ether. 2M HCl in diethyl ether (2.0 ml) was added to the solution of the above, and the mixed solution was stirred at room temperature for 3 hours. The reaction mixture is concentrated under reduced pressure, washed with diethyl ether and washed with 4- (4- (tert-butylamino) piperidine-1-yl) -2- (4-chlorobenzylamino) quinoline-3-carboxylic acid. A 43 mg (93% yield) off-white solid corresponding to the methyl hydrochloride was obtained.
Mass: (ES +) C ₂₇ H ₃₄ Cl ₂ N ₄ O ₂ Calculated value 480 (M-HCl) Measured value 481 [M + H], HPLC / MS Method 4.

Preparation of compound 564: 2- (4-chlorobenzylamino) -4- [4- (tert-butylamino) piperidine-1-yl] -7-methyl-8-fluoroquinoline hydrochloride

２−フルオロ−３−メチルアニリン（５．０ｇ、４０ｍｍｏｌ）に塩化ホスホリル（１００ｍｌ）を加え、次にマロン酸（１２．４ｇ、１２０ｍｍｏｌ）を少しずつ加えた。得られた混合液を８０℃で１時間撹拌した。次に、混合液を１２５℃で２時間撹拌した。反応混合液を室温にし、氷水に注ぎ、ＡｃＯＥｔ（２×１００ｍｌ）で抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、粗化合物を得て、これを、フラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＡｃＯＥｔ−石油エーテル；８：９２→１０：９０）により精製して、２，４−ジクロロ−８−フルオロ−７−メチルキノリンに対応する２．５ｇ（収率２７％）の白色固体を得た。
質量：ES+) C₁₀H₆Cl₂FN, 計算値 229; 実測値 230 [M+H], HPLC/MS 方法２。 Synthesis of 2,4-dichloro-7-methyl-8-fluoro-quinoline, intermediate 564-I-1

Phosphoryl chloride (100 ml) was added to 2-fluoro-3-methylaniline (5.0 g, 40 mmol), followed by malonic acid (12.4 g, 120 mmol) in portions. The obtained mixed solution was stirred at 80 ° C. for 1 hour. Next, the mixed solution was stirred at 125 ° C. for 2 hours. The reaction mixture was brought to room temperature, poured into ice water, and extracted with AcOEt (2 × 100 ml). The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a crude compound, which was subjected to flash chromatography (silica gel: 100-200 mesh, AcOEt-petroleum ether; 8 :). Purification by 92 → 10: 90) gave 2.5 g (yield 27%) of white solid corresponding to 2,4-dichloro-8-fluoro-7-methylquinoline.
Mass: ES +) C ₁₀ H ₆ Cl ₂ FN, Calculated 229; Measured 230 [M + H], HPLC / MS Method 2.

１，４−ジオキサン（２５ｍｌ）中の２，４−ジクロロ−７−メチル−８−フルオロ−キノリン（２．５ｇ、１０．９ｍｍｏｌ）の窒素ガス下の溶液に、４−クロロベンジルアミン（２．３ｇ、１６．３ｍｍｏｌ）及び炭酸セシウム（８．８ｇ、２７．２ｍｍｏｌ）を加えた。得られた混合液をアルゴンガスで３０分間脱気し、次にキサントホス（６３０ｍｇ、１．０９ｍｍｏｌ）及びＰｄ_２（ｄｂａ）_３（９９０ｍｇ、１．０９ｍｍｏｌ）を加え、反応混合液を１００℃で３時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、減圧下で濃縮した。残留物を食塩水とＡｃＯＥｔに分配し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、褐色油状物を得た。粗化合物を、フラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＡｃＯＥｔ−石油エーテル；１２：８８→１５：８５）により精製して、２−（４−クロロベンジルアミノ）−４−クロロ−７−メチル−８−フルオロキノリンに対応する１．１ｇ（収率３１％）の白色の固体を得た。
質量：(ES+) C₁₇H₁₃Cl₂FN₂ 計算値 334; 実測値 335 [M+H], HPLC/MS 方法４。 Synthesis of 2- (4-chlorobenzylamino) -4-chloro-7-methyl-8-fluoroquinoline, intermediate 564-I-2

In a solution of 2,4-dichloro-7-methyl-8-fluoro-quinoline (2.5 g, 10.9 mmol) in 1,4-dioxane (25 ml) under nitrogen gas, 4-chlorobenzylamine (2. 3 g, 16.3 mmol) and cesium carbonate (8.8 g, 27.2 mmol) were added. The obtained mixture is degassed with argon gas for 30 minutes, then xantphos (630 mg, _{1.09 mmol) and Pd 2} (dba) ₃ (990 mg, 1.09 mmol) are added, and the reaction mixture is mixed at 100 ° C. for 3 Stir for hours. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned into saline and AcOEt, and the aqueous layer was extracted with AcOEt. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown oil. The crude compound was purified by flash chromatography (silica gel: 100-200 mesh, AcOEt-petroleum ether; 12:88 → 15:85) and 2- (4-chlorobenzylamino) -4-chloro-7-methyl. A white solid of 1.1 g (31% yield) corresponding to -8-fluoroquinoline was obtained.
Mass: (ES +) C ₁₇ H ₁₃ Cl ₂ FN ₂ Calculated value 334; Measured value 335 [M + H], HPLC / MS Method 4.

２ｍｌのＮＭＰ中の２−（４−クロロベンジルアミノ）−４−クロロ−７−メチル−８−フルオロキノリン（０．２ｇ、０．５９８ｍｍｏｌ）の溶液に、４−（ｔｅｒｔ−ブチルアミノ）−ピペリジン（０．３２ｇ、２．０５ｍｍｏｌ）を加え、混合液をマイクロ波オーブン中で２００℃で４５分間加熱した。次に、反応混合液を氷水で冷却、希釈し、濾過し、集めた固体を分取ＨＰＬＣで精製して、２−（４−クロロベンジルアミノ）−４−［４−（ｔｅｒｔ−ブチルアミノ）ピペリジン−１−イル］−７−メチル−８−フルオロキノリンに対応する６０ｍｇ（収率２５％）の白色固体を得た。
質量：ES+) C₂₆H₃₂ClFN₄, 計算値 454; 実測値 455 [M +H], HPLC/MS 方法２。 2- (4-Chlorobenzylamino) -4- [4- (tert-butylamino) piperidine-1-yl] -7-methyl-8-fluoroquinoline, synthesis of the free base of the compound of Example 564

4- (tert-Butylamino) -piperidine in a solution of 2- (4-chlorobenzylamino) -4-chloro-7-methyl-8-fluoroquinoline (0.2 g, 0.598 mmol) in 2 ml of NMP. (0.32 g, 2.05 mmol) was added and the mixture was heated in a microwave oven at 200 ° C. for 45 minutes. Next, the reaction mixture is cooled with ice water, diluted, filtered, and the collected solid is purified by preparative HPLC to 2- (4-chlorobenzylamino) -4- [4- (tert-butylamino). A 60 mg (25% yield) white solid corresponding to piperidine-1-yl] -7-methyl-8-fluoroquinoline was obtained.
Mass: ES +) C ₂₆ H ₃₂ ClFN ₄ , Calculated value 454; Measured value 455 [M + H], HPLC / MS Method 2.

４ｍｌのジエチルエーテル中の２−（４−クロロベンジルアミノ）−４−［４−（ｔｅｒｔ−ブチルアミノ）ピペリジン−１−イル］−７−メチル−８−フルオロキノリン（０．０６ｇ）の溶液に、ジエチルエーテル（１．０ｍｌ）中の２Ｍ ＨＣｌを加え、混合液を室温で３時間撹拌した。反応混合液を減圧下で濃縮し、ジエチルエーテルで洗浄して、２−（４−クロロベンジルアミノ）−４−［４−（ｔｅｒｔ−ブチルアミノ）ピペリジン−１−イル］−ピペリジン−１−イル］−７−メチル−８−フルオロキノリン塩酸塩に対応する５０ｍｇ（収率７２％）のオフホワイトの固体を得た。
質量：(ES+) C₂₆H₃₂ClFN₄ 計算値 454(M-HCl) ; 実測値 455 [M +H], HPLC/MS ＨＰＬＣ／ＭＳ 方法２。 Synthesis of 564 compounds, 2- (4-chlorobenzylamino) -4- [4- (tert-butylamino) piperidine-1-yl] -7-methyl-8-fluoroquinoline hydrochloride

In a solution of 2- (4-chlorobenzylamino) -4- [4- (tert-butylamino) piperidine-1-yl] -7-methyl-8-fluoroquinoline (0.06 g) in 4 ml of diethyl ether. , 2M HCl in diethyl ether (1.0 ml) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture is concentrated under reduced pressure, washed with diethyl ether, and 2- (4-chlorobenzylamino) -4- [4- (tert-butylamino) piperidine-1-yl] -piperidine-1-yl. ] A 50 mg (72% yield) off-white solid corresponding to -7-methyl-8-fluoroquinoline hydrochloride was obtained.
Mass: (ES +) C ₂₆ H ₃₂ ClFN ₄ Calculated value 454 (M-HCl); Measured value 455 [M + H], HPLC / MS HPLC / MS Method 2.

Compound 568: Preparation of 2- (4-chlorobenzylamino) -4- [4- (tert-butylamino) piperidine-1-yl] -6-methyl-8-fluoroquinoline, hydrochloride

２−フルオロ−３−メチルアニリン（２．０ｇ、１６ｍｍｏｌ）に塩化ホスホリル（４０ｍｌ）を加え、次にマロン酸（２．４ｇ、２４ｍｍｏｌ）を少しずつ加えた。得られた混合液を８０℃で１６時間撹拌した。反応混合液を室温にし、氷水混合液に注いだ。水層をＡｃＯＥｔ（２×５０ｍｌ）で抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して粗化合物を得て、これをフラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＡｃＯＥｔ−石油エーテル；２：９８→５：９５）により精製して、２，４−ジクロロ−６−メチル−８−フルオロキノリンに対応する７００ｍｇ（収率１９％）の白色固体を得た。
質量：(ES+) C₁₀H₆Cl₂FN計算値 229; 実測値 230 [M+H], HPLC/MS 方法２。 Synthesis of 2,4-dichloro-6-methyl-8-fluoro-quinoline intermediate 568-I-1

Phosphoryl chloride (40 ml) was added to 2-fluoro-3-methylaniline (2.0 g, 16 mmol), followed by malonic acid (2.4 g, 24 mmol) in small portions. The obtained mixed solution was stirred at 80 ° C. for 16 hours. The reaction mixture was brought to room temperature and poured into an ice-water mixture. The aqueous layer was extracted with AcOEt (2 x 50 ml). The combined organic layer was _{dried with Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a crude compound, which was subjected to flash chromatography (silica gel: 100-200 mesh, AcOEt-petroleum ether; 2:98 → Purification according to 5:95) gave 700 mg (19% yield) of white solid corresponding to 2,4-dichloro-6-methyl-8-fluoroquinoline.
Mass: (ES +) C ₁₀ H ₆ Cl ₂ FN Calculated 229; Measured 230 [M + H], HPLC / MS Method 2.

１，４−ジオキサン（１０ｍｌ）中の２，４−ジクロロ−６−メチル−８−フルオロキノリン（３００ｍｇ、１．３１ｍｍｏｌ）の窒素ガス下の溶液に、４−クロロベンジルアミン（２２１ｍｇ、１．５７ｍｍｏｌ）及び炭酸セシウム（８５９ｍｇ、２．６２ｍｍｏｌ）を加えた。得られた反応混合液をアルゴンガスで１０分間脱気し、次にキサントホス（７５ｍｇ、０．１３１ｍｍｏｌ）及びＰｄ_２（ｄｂａ）_３（１１９ｍｇ、０．１３１ｍｍｏｌ）を加え、反応混合液を１００℃で３時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、減圧下で濃縮した。残留物を食塩水とＡｃＯＥｔに分配し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して褐色油状物を得た。粗化合物をフラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＡｃＯＥｔ−石油エーテル；１２：８８→１５：８５）により精製して、２−（４−クロロベンジルアミノ）−４−クロロ−６−メチル−８−フルオロキノリンに対応する１００ｍｇ（収率２２％）のオフホワイトの固体を得た。
質量：(ES+) C₁₇H₁₃Cl₂FN₂ 計算値 334; 実測値 335 [M+H], HPLC/MS 方法２。 Synthesis of 2- (4-chlorobenzylamino) -4- [4- (tert-butylamino) piperidine-1-yl] -6-methyl-8-fluoroquinoline, intermediate 568-I-2

4-Chlorobenzylamine (221 mg, 1.57 mmol) in a solution of 2,4-dichloro-6-methyl-8-fluoroquinoline (300 mg, 1.31 mmol) in 1,4-dioxane (10 ml) under nitrogen gas. ) And cesium carbonate (859 mg, 2.62 mmol) were added. The obtained reaction mixture was degassed with argon gas for 10 minutes, then xantphos (75 mg, 0.131 mmol) and Pd ₂ (dba) ₃ (119 mg, 0.131 mmol) were added, and the reaction mixture was added at 100 ° C. The mixture was stirred for 3 hours. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned into saline and AcOEt, and the aqueous layer was extracted with AcOEt. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown oil. The crude compound was purified by flash chromatography (silica gel: 100-200 mesh, AcOEt-petroleum ether; 12:88 → 15:85) and 2- (4-chlorobenzylamino) -4-chloro-6-methyl- A 100 mg (22% yield) off-white solid corresponding to 8-fluoroquinoline was obtained.
Mass: (ES +) C ₁₇ H ₁₃ Cl ₂ FN ₂ Calculated value 334; Measured value 335 [M + H], HPLC / MS Method 2.

２ｍｌのＮＭＰ中の２−（４−クロロベンジルアミノ）−４−クロロ−６−メチル−８−フルオロキノリン（１００ｍｇ、０．２９９ｍｍｏｌ）の溶液に、４−（ｔｅｒｔ−ブチルアミノ）−ピペリジン（０．１６３ｍｇ、１．０４ ｍｍｏｌ）を加え、混合液をマイクロ波オーブン中で２００℃で３時間加熱した。次に、反応混合液を氷水で冷却、希釈し、濾過した。集めた固体を分取ＨＰＬＣで精製して、２−（４−クロロベンジルアミノ）−４−［４−（ｔｅｒｔ−ブチルアミノ）ピペリジン−１−イル］−６−メチル−８−フルオロキノリンに対応する４０ｍｇ（収率２９％）のオフホワイトの固体を得た。
質量：(ES+) C₂₆H₃₂ClFN₄ 計算値 454; 実測値 455 [M+H], HPLC/MS 方法２。 Synthesis of the free base of compound 568, 2- (4-chlorobenzylamino) -4- [4- (tert-butylamino) piperidine-1-yl] -6-methyl-8-fluoroquinoline.

4- (tert-Butylamino) -piperidine (0) in a solution of 2- (4-chlorobenzylamino) -4-chloro-6-methyl-8-fluoroquinoline (100 mg, 0.299 mmol) in 2 ml of NMP. .163 mg, 1.04 mmol) was added and the mixture was heated in a microwave oven at 200 ° C. for 3 hours. Next, the reaction mixture was cooled with ice water, diluted, and filtered. The collected solids are purified by preparative HPLC to accommodate 2- (4-chlorobenzylamino) -4- [4- (tert-butylamino) piperidine-1-yl] -6-methyl-8-fluoroquinoline. 40 mg (29% yield) of off-white solid was obtained.
Mass: (ES +) C ₂₆ H ₃₂ ClFN ₄ Calculated value 454; Measured value 455 [M + H], HPLC / MS Method 2.

５ｍｌのＤＣＭ中の２−（４−クロロベンジルアミノ）−４−［４−（ｔｅｒｔ−ブチルアミノ）ピペリジン−１−イル］−６−メチル−８−フルオロキノリン（０．０４ｇ、０．０８８ｍｍｏｌ）の溶液に、ジエチルエーテル（２．０ｍｌ）中の１Ｍ ＨＣｌに加え、混合液を室温で１時間撹拌した。反応混合液を減圧下で濃縮し、ジエチルエーテルで洗浄して、２−（４−クロロベンジルアミノ）−４−［４−（ｔｅｒｔ−ブチルアミノ）ピペリジン−１−イル］−６−メチル−８−フルオロキノリン塩酸塩に対応する３５ｍｇ（収率８１％）のオフホワイトの固体を得た。
質量：ES+) C₂₆H₃₂ClFN₄ 計算値 454 (M-HCl) ; 実測値 455[M +H], HPLC/MS 方法２。 Compound 568: Synthesis of 2- (4-chlorobenzylamino) -4- [4- (tert-butylamino) piperidine-1-yl] -6-methyl-8-fluoroquinoline hydrochloride

2- (4-Chlorobenzylamino) -4- [4- (tert-butylamino) piperidine-1-yl] -6-methyl-8-fluoroquinoline (0.04 g, 0.088 mmol) in 5 ml DCM To the solution of 1M HCl in diethyl ether (2.0 ml), the mixture was stirred at room temperature for 1 hour. The reaction mixture is concentrated under reduced pressure, washed with diethyl ether, and 2- (4-chlorobenzylamino) -4- [4- (tert-butylamino) piperidine-1-yl] -6-methyl-8. -A 35 mg (81% yield) off-white solid corresponding to fluoroquinoline hydrochloride was obtained.
Mass: ES +) C ₂₆ H ₃₂ ClFN ₄ Calculated value 454 (M-HCl); Measured value 455 [M + H], HPLC / MS Method 2.

Preparation of Compound 572: 2- (4-chlorobenzylamino) -4- [4- (tert-butylamino) piperidine-1-yl] -7-fluoro-8-methylquinoline hydrochloride

２−フルオロ−３−メチルアニリン（２．０ｇ、１６ｍｍｏｌ）に塩化ホスホリル（４０ｍｌ）を加え、次にマロン酸（２．４ｇ、２４ｍｍｏｌ）を少しずつ加えた。得られた混合液を８０℃で１６時間撹拌した。反応混合液を室温にし、氷水混合液に注いだ。水層をＡｃＯＥｔ（２×５０ｍｌ）で抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して粗化合物を得て、これをフラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＡｃＯＥｔ−石油エーテル；２：９８→５：９５）により精製して、２，４−ジクロロ−７−フルオロ−８−メチルキノリンに対応する１．２ｇ（収率３３％）の白色固体を得た。
質量：（((ES+) C₂₆H₃₂ClFN₄ 計算値 229; 実測値 230 [M +H], HPLC/MS 方法４。 Synthesis of 2,4-dichloro-7-fluoro-8-methylquinoline intermediate 572-I-1

Phosphoryl chloride (40 ml) was added to 2-fluoro-3-methylaniline (2.0 g, 16 mmol), followed by malonic acid (2.4 g, 24 mmol) in small portions. The obtained mixed solution was stirred at 80 ° C. for 16 hours. The reaction mixture was brought to room temperature and poured into an ice-water mixture. The aqueous layer was extracted with AcOEt (2 x 50 ml). The combined organic layer was _{dried with Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a crude compound, which was subjected to flash chromatography (silica gel: 100-200 mesh, AcOEt-petroleum ether; 2:98 → Purification according to 5:95) gave 1.2 g (33% yield) of white solid corresponding to 2,4-dichloro-7-fluoro-8-methylquinoline.
Mass: (((ES +) C ₂₆ H ₃₂ ClFN ₄ Calculated 229; Measured 230 [M + H], HPLC / MS Method 4.

１，４−ジオキサン（１０ｍｌ）中の２，４−ジクロロ−７−フルオロ−８−メチルキノリン（６５０ｍｇ、２．８２ｍｍｏｌ）の窒素ガス下の溶液に、４−クロロベンジルアミン（４７８ｍｇ、３．３９ｍｍｏｌ）及び炭酸セシウム（１．８４ｍｇ、５．６４ｍｍｏｌ）を加えた。得られた混合液をアルゴンガスで１０分間脱気し、次にキサントホス（１６２ｍｇ、０．２８２ｍｍｏｌ）及びＰｄ_２（ｄｂａ）_３（２５８ｍｇ、０．２８２ｍｍｏｌ）を加え、反応混合液を１００℃で３時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、減圧下で濃縮した。残留物を食塩水とＡｃＯＥｔに分配し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、褐色油状物を得た。粗化合物をフラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＡｃＯＥｔ−石油エーテル；１０：９０→１５：８５）により精製して、２−（４−クロロベンジルアミノ）−４−クロロ−７−フルオロ−８−メチルキノリンに対応する３５０ｍｇ（収率３５％）のオフホワイトの固体を得た。
質量：(ES+) C₂₆H₃₂ClFN₄ 計算値 334; 実測値 335 [M +H], HPLC/MS 方法４。 Synthesis of 2- (4-chlorobenzylamino) -4-chloro-7-fluoro-8-methylquinoline, intermediate 572-I-2

4-Chlorobenzylamine (478 mg, 3.39 mmol) in a solution of 2,4-dichloro-7-fluoro-8-methylquinoline (650 mg, 2.82 mmol) under nitrogen gas in 1,4-dioxane (10 ml). ) And cesium carbonate (1.84 mg, 5.64 mmol) were added. The resulting mixture was degassed with argon gas for 10 minutes, then xantphos (162 mg, 0.282 mmol) and Pd ₂ (dba) ₃ (258 mg, 0.282 mmol) were added, and the reaction mixture was mixed at 100 ° C. for 3 Stir for hours. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned into saline and AcOEt, and the aqueous layer was extracted with AcOEt. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown oil. The crude compound was purified by flash chromatography (silica gel: 100-200 mesh, AcOEt-petroleum ether; 10:90 → 15:85) and 2- (4-chlorobenzylamino) -4-chloro-7-fluoro-. A 350 mg (35% yield) off-white solid corresponding to 8-methylquinoline was obtained.
Mass: (ES +) C ₂₆ H ₃₂ ClFN ₄ Calculated value 334; Measured value 335 [M + H], HPLC / MS Method 4.

２ｍｌのＮＭＰ中の２−（４−クロロベンジルアミノ）−４−クロロ−７−フルオロ−８−メチルキノリン（２００ｍｇ、０．５９９ｍｍｏｌ）の溶液に、４−（ｔｅｒｔ−ブチルアミノ）ピペリジン（０．２９９ｍｇ、１．９４ ｍｍｏｌ）を加え、次に混合液をマイクロ波オーブン中で２００℃で３時間加熱した。次に、反応混合液を氷水で冷却、希釈し、濾過した。集めた固体を分取ＨＰＬＣにより精製して、２−（４−クロロベンジルアミノ）−４−［４−（ｔｅｒｔ−ブチルアミノ）ピペリジン−１−イル］−７−フルオロ−８−メチルキノリンに対応する８０ｍｇ（収率３０％）のオフホワイトの固体を得た。
質量：(ES+) C₂₆H₃₂ClFN₄ 計算値 454; 実測値 455 [M +H], HPLC/MS 方法４。 Synthesis of the free base of compound 572, 2- (4-chlorobenzylamino) -4- [4- (tert-butylamino) piperidine-1-yl] -7-fluoro-8-methylquinoline.

In a solution of 2- (4-chlorobenzylamino) -4-chloro-7-fluoro-8-methylquinoline (200 mg, 0.599 mmol) in 2 ml of NMP, 4- (tert-butylamino) piperidine (0. 299 mg (1.94 mmol) was added, and then the mixture was heated in a microwave oven at 200 ° C. for 3 hours. Next, the reaction mixture was cooled with ice water, diluted, and filtered. The collected solids are purified by preparative HPLC to accommodate 2- (4-chlorobenzylamino) -4- [4- (tert-butylamino) piperidine-1-yl] -7-fluoro-8-methylquinoline. 80 mg (30% yield) of off-white solid was obtained.
Mass: (ES +) C ₂₆ H ₃₂ ClFN ₄ Calculated 454; Measured 455 [M + H], HPLC / MS Method 4.

４ｍｌのエーテル中の２−（４−クロロベンジルアミノ）−４−［４−（ｔｅｒｔ−ブチルアミノ）ピペリジン−１−イル］−７−フルオロ−８−メチルキノリン（８０ｍｇ、０．１７５ｍｍｏｌ）の溶液に、Ｅｔ_２Ｏ（２．０ｍｌ）中の４Ｍ ＨＣｌを加え、混合液を室温で３時間撹拌した。反応混合液を減圧下で濃縮し、ジエチルエーテルで洗浄して、２−（４−クロロベンジルアミノ）−４−［４−（ｔｅｒｔ−ブチルアミノ）ピペリジン−１−イル］−７−フルオロ−８−メチルキノリン塩酸塩に対応する７０ｍｇ（収率８２％）のオフホワイトの固体を得た。
質量：(ES+) C₂₆H₃₂ClFN₄ 計算値 454 (M-HCl); 実測値 455 [M +H], HPLC/MS 方法２。 Synthesis of Compounds 572, 2- (4-Chlorobenzylamino) -4- [4- (tert-butylamino) piperidine-1-yl] -7-fluoro-8-methylquinoline hydrochloride

A solution of 2- (4-chlorobenzylamino) -4- [4- (tert-butylamino) piperidine-1-yl] -7-fluoro-8-methylquinoline (80 mg, 0.175 mmol) in 4 ml of ether. 4M HCl in Et ₂ O (2.0 ml) was added to the mixture, and the mixed solution was stirred at room temperature for 3 hours. The reaction mixture is concentrated under reduced pressure, washed with diethyl ether, and 2- (4-chlorobenzylamino) -4- [4- (tert-butylamino) piperidine-1-yl] -7-fluoro-8. -70 mg (82% yield) of off-white solid corresponding to methylquinoline hydrochloride was obtained.
Mass: (ES +) C ₂₆ H ₃₂ ClFN ₄ Calculated value 454 (M-HCl); Measured value 455 [M + H], HPLC / MS Method 2.

Preparation of Compounds 580, 2- (4-Chlorobenzylamino) -4- [4- (tert-butylamino) piperidine-1-yl] -6-fluoro-8-methylquinoline, hydrochloride

２−フルオロ−３−メチルアニリン（２．５ｇ、２０ｍｍｏｌ）に塩化ホスホリル（４０ｍｌ）を加え、次にマロン酸（４．２ｇ、４０ｍｍｏｌ）を少しずつ加えた。得られた反応混合液を８０℃で１６時間撹拌した。次に、反応混合液を室温にし、氷水に注いだ。水層をＡｃＯＥｔ（２×５０ｍｌ）で抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して粗化合物を得て、これをフラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＡｃＯＥｔ−石油エーテル；２：９８→５：９５）似いい精製して、２，４−ジクロロ−６−フルオロ−８−メチルキノリンに対応する０．７５ｇ（収率２０％）の白色固体を得た。
質量：(ES+) C₂₆H₃₂ClFN₄ 計算値 229; 実測値 230 [M +H], HPLC/MS 方法４。 Synthesis of 2,4-dichloro-6-fluoro-8-methylquinoline, intermediate 580-I-1

Phosphoryl chloride (40 ml) was added to 2-fluoro-3-methylaniline (2.5 g, 20 mmol), then malonic acid (4.2 g, 40 mmol) was added in portions. The obtained reaction mixture was stirred at 80 ° C. for 16 hours. Next, the reaction mixture was brought to room temperature and poured into ice water. The aqueous layer was extracted with AcOEt (2 x 50 ml). The combined organic layer was _{dried with Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a crude compound, which was subjected to flash chromatography (silica gel: 100-200 mesh, AcOEt-petroleum ether; 2:98 → 5:95) Similar purification gave 0.75 g (20% yield) of white solid corresponding to 2,4-dichloro-6-fluoro-8-methylquinoline.
Mass: (ES +) C ₂₆ H ₃₂ ClFN ₄ Calculated 229; Measured 230 [M + H], HPLC / MS Method 4.

１，４−ジオキサン（１０ｍｌ）中の２，４−ジクロロ−６−フルオロ−８−メチルキノリン（７５０ｍｇ、３．２６ｍｍｏｌ）の窒素ガス下の溶液に、４−クロロベンジルアミン（５５０ｍｇ、３．９１ｍｍｏｌ）及びｔ−ＢｕＯＮａ（０．７８ｇ、８．１５ｍｍｏｌ）を加えた。得られた混合液を窒素で５分間脱気し、次にキサントホス（１８８ｍｇ、０．３２ｍｍｏｌ）及びＰｄ（ＯＡｃ）_２（３６ｍｇ、０．１６ｍｍｏｌ）を加え、反応混合液を２時間加熱還流した。次に、反応混合液を室温に冷却し、減圧下で濃縮した。残留物を食塩水とＡｃＯＥｔに分配し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、褐色油状物を得た。粗化合物をフラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＡｃＯＥｔ−石油エーテル；１０：９０→１５：８５）により精製して、２−（４−クロロベンジルアミノ）−４−クロロ−６−フルオロ−８−メチルキノリンに対応する５５０ｍｇ（収率５５％）のオフホワイトの固体を得た。
質量：(ES+) C₂₆H₃₂ClFN₄ 計算値 334; 実測値 335 [M +H], HPLC/MS 方法４。 Synthesis of 2- (4-chlorobenzylamino) -4-chloro-6-fluoro-8-methylquinoline, intermediate 580-I-2

4-Chlorobenzylamine (550 mg, 3.91 mmol) in a solution of 2,4-dichloro-6-fluoro-8-methylquinoline (750 mg, 3.26 mmol) under nitrogen gas in 1,4-dioxane (10 ml). ) And t-BuONa (0.78 g, 8.15 mmol) were added. The obtained mixture was degassed with nitrogen for 5 minutes, then xantphos (188 mg, 0.32 mmol) and Pd (OAc) ₂ (36 mg, 0.16 mmol) were added, and the reaction mixture was heated to reflux for 2 hours. Next, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned into saline and AcOEt, and the aqueous layer was extracted with AcOEt. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown oil. The crude compound was purified by flash chromatography (silica gel: 100-200 mesh, AcOEt-petroleum ether; 10:90 → 15:85) and 2- (4-chlorobenzylamino) -4-chloro-6-fluoro-. An off-white solid of 550 mg (55% yield) corresponding to 8-methylquinoline was obtained.
Mass: (ES +) C ₂₆ H ₃₂ ClFN ₄ Calculated value 334; Measured value 335 [M + H], HPLC / MS Method 4.

２ｍｌのＮＭＰ中の２−（４−クロロベンジルアミノ）−４−クロロ−６−フルオロ−８−メチルキノリン（１５０ｍｇ、０．４４ｍｍｏｌ）の溶液に、４−（ｔｅｒｔ−ブチルアミノ）ピペリジン（０．２０９ｍｇ、１．３４ ｍｍｏｌ）を加え、得られた混合液をマイクロ波オーブン中で２００℃で３時間加熱した。次に、反応混合液を氷水で冷却、希釈し、濾過した。集めた固体を分取ＨＰＬＣにより精製して、２−（４−クロロベンジルアミノ）−４−［４−（ｔｅｒｔ−ブチルアミノ）ピペリジン−１−イル］−６−フルオロ−８−メチルキノリンに対応する１００ｍｇ（収率５０％）のオフホワイトの固体を得た。
質量：((ES+) C₂₆H₃₂ClFN₄ 計算値 454; 実測値 455 [M +H], HPLC/MS 方法５。 Synthesis of the free base of compound 580, 2- (4-chlorobenzylamino) -4- [4- (tert-butylamino) piperidine-1-yl] -6-fluoro-8-methylquinoline.

In a solution of 2- (4-chlorobenzylamino) -4-chloro-6-fluoro-8-methylquinoline (150 mg, 0.44 mmol) in 2 ml of NMP, 4- (tert-butylamino) piperidine (0. 209 mg (1.34 mmol) was added, and the resulting mixture was heated in a microwave oven at 200 ° C. for 3 hours. Next, the reaction mixture was cooled with ice water, diluted, and filtered. The collected solids are purified by preparative HPLC to accommodate 2- (4-chlorobenzylamino) -4- [4- (tert-butylamino) piperidine-1-yl] -6-fluoro-8-methylquinoline. 100 mg (50% yield) of off-white solid was obtained.
Mass: ((ES +) C ₂₆ H ₃₂ ClFN ₄ Calculated 454; Measured 455 [M + H], HPLC / MS Method 5.

４ｍｌのエーテル中の２−（４−クロロベンジルアミノ）−４−［４−（ｔｅｒｔ−ブチルアミノ）ピペリジン−１−イル］−６−フルオロ−８−メチルキノリン（０．１ｇ、０．２２ｍｍｏｌ）の溶液に、Ｅｔ_２Ｏ（２．０ｍｌ）中の４Ｍ ＨＣｌを加え、得られた混合液を室温で３時間撹拌した。反応混合液を減圧濃縮し、ジエチルエーテルで洗浄して、２−（４−クロロベンジルアミノ）−４−［４−（ｔｅｒｔ−ブチルアミノ）ピペリジン−１−イル］−６−フルオロ−８−メチルキノリン塩酸塩に対応する９０ｍｇ（収率８２％）のオフホワイトの固体を得た。
質量：( ES+) C₂₆H₃₂ClFN₄ 計算値 454 (M-HCl) ; 実測値 455 [M +H], HPLC/MS 方法２。 Synthesis of Compounds 580, 2- (4-Chlorobenzylamino) -4- [4- (tert-butylamino) piperidine-1-yl] -6-fluoro-8-methylquinoline hydrochloride

2- (4-Chlorobenzylamino) -4- [4- (tert-butylamino) piperidine-1-yl] -6-fluoro-8-methylquinoline (0.1 g, 0.22 mmol) in 4 ml of ether. 4M HCl in Et ₂ O (2.0 ml) was added to the solution of, and the obtained mixed solution was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, washed with diethyl ether, and 2- (4-chlorobenzylamino) -4- [4- (tert-butylamino) piperidine-1-yl] -6-fluoro-8-methyl. A 90 mg (82% yield) off-white solid corresponding to quinoline hydrochloride was obtained.
Mass: (ES +) C ₂₆ H ₃₂ ClFN ₄ Calculated value 454 (M-HCl); Measured value 455 [M + H], HPLC / MS Method 2.

Preparation of compound of 532-Me, 2- [4- (4-methylpyrimidine-2-ylamino) phenylamino] -3-methyl-4- (4-tert-butylaminopiperidine-1-yl) quinoline hydrochloride

０℃で１０％エタノール水溶液（１００ｍｌ）中のベンゼン−１，４−ジアミン（５．０ｇ、４６．２９ｍｍｏｌ）及び２−クロロ−４−メチルピリミジン（５．９ｇ、４６．２９ｍｍｏｌ）の撹拌溶液に、濃ＨＣｌ水溶液（３．４ｍｌ、９２．５８ｍｍｏｌ）を滴加した。得られた反応混合液を１００℃で２時間撹拌した。溶媒を留去し、得られた残留物を冷水で希釈し、１０％ＮａＨＣＯ_３水溶液で中和し、ＡｃＯＥｔ（２×１００ｍｌ）で抽出した。合わせた有機層を食塩水（５０ｍｌ）で洗浄し、Ｎａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、粗化合物を得て、これを、フラッシュクロマトグラフィー（REVELERIS-Grace ４０ｇ、シリカゲル：２３０〜４００メッシュ、ＡｃＯＥｔ−石油エーテル；１：４→３：７）により精製して、Ｎ^１−（４−メチルピリミジン−２−イル）ベンゼン−１，４−ジアミンに対応する３ｇ（収率３２％）の淡褐色固体を得た。
質量：ES+) C₁₁H₁₂N₄, 計算値 200; 実測値 201.1 [M+H], HPLC/MS 方法５。 N ¹ - (4-methyl-pyrimidin-2-yl) benzene-1,4-diamine, synthesis of intermediate 532-Me-I-1

In a stirred solution of benzene-1,4-diamine (5.0 g, 46.29 mmol) and 2-chloro-4-methylpyrimidine (5.9 g, 46.29 mmol) in a 10% aqueous ethanol solution (100 ml) at 0 ° C. , Concentrated HCl aqueous solution (3.4 ml, 92.58 mmol) was added dropwise. The obtained reaction mixture was stirred at 100 ° C. for 2 hours. The solvent was distilled off, the obtained residue was diluted with cold water _{, neutralized with 10% aqueous NaHCO 3} solution, and extracted with AcOEt (2 × 100 ml). The combined organic layers were washed with saline (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude compound, which was subjected to flash chromatography (REVELERIS-Grace 40 g, 40 g). silica gel: 230-400 mesh, AcOEt-petroleum ether; 1: 4 → 3: 7 ) to ^give, N 1 - (4-methyl-pyrimidin-2-yl) 3 g corresponding to benzene-1,4-diamine ( A light brown solid with a yield of 32%) was obtained.
Mass: ES +) C ₁₁ H ₁₂ N ₄ , Calculated value 200; Measured value 201.1 [M + H], HPLC / MS Method 5.

ＴＨＦ（２０ｍｌ）中の２，４−ジクロロ−３−メチルキノリン（０．５ｇ、２．３５ｍｍｏｌ）のアルゴンガス下の溶液に、Ｎ^１−（４−メチルピリミジン−２−イル）ベンゼン−１，４−ジアミン（０．５７ｇ、２．８３ｍｍｏｌ）及びｔ−ＢｕＯＮａ（０．６３ｇ、６．５８ｍｍｏｌ）を加えた。得られた混合液をアルゴンガスで１０分間脱気し、次にキサントホス（０．１４ｇ、０．２３ｍｍｏｌ）及びＰｄ（ＯＡｃ）_２（２７ｍｇ、０．１２ｍｍｏｌ）を加え、次に反応混合液を８０℃で３時間撹拌した。次に、反応混合液を室温に冷却し、冷水（３０ｍｌ）で希釈し、ＡｃＯＥｔ（２×５０ｍｌ）で抽出した。合わせた有機層を食塩水（３０ｍｌ）で洗浄し、Ｎａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して褐色油状物を得て、これをフラッシュクロマトグラフィー（REVELERIS-Grace、４０ｇ、シリカゲル：２３０〜４００メッシュ、ＡｃＯＥｔ−石油エーテル１：４→３：７）により精製して、２−［４−（４−メチルピリミジン−２−イルアミノ）フェニルアミノ］−３−メチル４−クロロキノリンに対応する０．１８ｇ（２０％収率）の淡褐色の固体を得た。
質量：(ES+) C₂₁H₁₈ClN₅ 計算値 375.13; 実測値 376.1 [M+H], method HPLC/MS 方法６。 Synthesis of 2- [4- (4-methylpyrimidine-2-ylamino) phenylamino] -3-methyl-4-chloroquinoline, intermediate 532-Me-I-2

THF (20 ml) solution of 2,4-dichloro-3-methylquinoline (0.5 g, 2.35 mmol) to a solution under argon ^of, N 1 - (4-methyl-pyrimidin-2-yl) benzene-1, 4-Diamine (0.57 g, 2.83 mmol) and t-BuONa (0.63 g, 6.58 mmol) were added. The obtained mixture is degassed with argon gas for 10 minutes, then xantphos (0.14 g, 0.23 mmol) and Pd (OAc) ₂ (27 mg, 0.12 mmol) are added, and then the reaction mixture is 80. The mixture was stirred at ° C. for 3 hours. The reaction mixture was then cooled to room temperature, diluted with cold water (30 ml) and extracted with AcOEt (2 x 50 ml). The combined organic layers were washed with saline (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a brown oil, which was subjected to flash chromatography (REVELERIS-Grace, 40 g, 40 g). Filtration: 230-400 mesh, purified with AcOEt-petroleum ether 1: 4 → 3: 7), 2- [4- (4-methylpyrimidine-2-ylamino) phenylamino] -3-methyl4-chloroquinoline A light brown solid of 0.18 g (20% yield) corresponding to the above was obtained.
Mass: (ES +) C ₂₁ H ₁₈ ClN ₅ Calculated value 375.13; Measured value 376.1 [M + H], method HPLC / MS Method 6.

３ｍｌのＮＭＰ中の２−［４−（４−メチルピリミジン−２−イルアミノ）フェニルアミノ］−３−メチル−４−クロロキノリン（０．４ｇ、１．０６ｍｍｏｌ）の溶液に、４−（ｔｅｒｔ−ブチルアミノ）−ピペリジン（０．８３ｇ、５．３０ｍｍｏｌ）を加え、次に混合液をマイクロ波オーブン中で２４０℃で４時間加熱した。次に、反応混合液を氷水で冷却、希釈し、濾過した。集めた固体をＳＦＣ分取クロマトグラフィーにより精製して、２−［４−（４−メチルピリミジン−２−イルアミノ）フェニルアミノ］−３−メチル−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリンに対応する７０ｍｇ（収率１３％）の淡黄色の固体を得た。
質量：(ES+) C₃₀H₃₇N₇, 計算値 495.31; 実測値 496.3 [M +H], HPLC/MS 方法５。 Synthesis of 2- [4- (4-methylpyrimidine-2-ylamino) phenylamino] -3-methyl-4- (4-tert-butylaminopiperidine-1-yl) quinoline, a free base of compound 532-Me

In a solution of 2- [4- (4-methylpyrimidine-2-ylamino) phenylamino] -3-methyl-4-chloroquinoline (0.4 g, 1.06 mmol) in 3 ml of NMP, 4- (tert- Butylamino) -piperidine (0.83 g, 5.30 mmol) was added and the mixture was then heated in a microwave oven at 240 ° C. for 4 hours. Next, the reaction mixture was cooled with ice water, diluted, and filtered. The collected solid was purified by SFC preparative chromatography and 2- [4- (4-methylpyrimidine-2-ylamino) phenylamino] -3-methyl-4- (4-tert-butylaminopiperidine-1-). Ill) A pale yellow solid of 70 mg (13% yield) corresponding to quinoline was obtained.
Mass: (ES +) C ₃₀ H ₃₇ N ₇ , Calculated value 495.31; Measured value 496.3 [M + H], HPLC / MS Method 5.

０℃の２ｍｌのエタノール中の２−［４−（４−メチルピリミジン−２−イルアミノ）フェニルアミノ］−３−メチル−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリン（０．０７ｇ、０．０９１ｍｍｏｌ）の溶液に、エタノール（２ｍｌ）中の７．２Ｍ ＨＣｌを加え、混合液を室温で１時間撹拌した。反応混合液を減圧下で濃縮し、ジエチルエーテルで洗浄して、２−［４−（４−メチルピリミジン−２−イルアミノ）フェニルアミノ］−３−メチル−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリン塩酸塩に対応する６０ｍｇ（収率８０％）の淡黄色固体を得た。
質量：(ES+) C₃₀H₃₈ClN₇ 計算値 531.29; 実測値 496.3 [(M-HCl + H)]⁺, HPLC 方法６。 Synthesis of Compounds 532-Me, 2- [4- (4-methylpyrimidine-2-ylamino) phenylamino] -3-methyl-4- (4-tert-butylaminopiperidine-1-yl) quinoline hydrochloride

2- [4- (4-Methylpyrimidine-2-ylamino) phenylamino] -3-methyl-4- (4-tert-butylaminopiperidin-1-yl) quinoline in 2 ml of ethanol at 0 ° C. 7.2M HCl in ethanol (2 ml) was added to a solution of 07 g, 0.091 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction mixture is concentrated under reduced pressure, washed with diethyl ether and 2- [4- (4-methylpyrimidine-2-ylamino) phenylamino] -3-methyl-4- (4-tert-butylaminopiperidine). A pale yellow solid of 60 mg (80% yield) corresponding to -1-yl) quinoline hydrochloride was obtained.
Mass: (ES +) C ₃₀ H ₃₈ ClN ₇ Calculated value 531.29; Measured value 496.3 [(M-HCl + H)] ⁺ , HPLC method 6.

Preparation of compound 540-Me: 2- [3- (4-trifluoromethylpyrimidine-2-ylamino) phenylamino] -3-methyl-4- (4-tert-butylaminopiperidine-1-yl) quinoline hydrochloride Preparation of

０℃の１０％エタノール水溶液中のベンゼン−１，３−ジアミン（２．０ｇ、１８．５１ｍｍｏｌ）及び２−クロロ−４−（トリフルオロメチル）ピリミジン（３．４ｇ、１８．５１ｍｍｏｌ）の撹拌溶液に、濃ＨＣｌ水溶液（１．１ｍｌ）を滴加し。次に、得られた混合液を１００℃で２時間撹拌した。次に、溶媒を留去し、得られた残留物を冷水で希釈し、１０％ＮａＨＣＯ_３で塩基性化し、ＡｃＯＥｔ（２×５０ｍｌ）で抽出した。合わせた有機層を食塩水（２０ｍｌ）で洗浄し、Ｎａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して粗化合物を得て、これを、フラッシュクロマトグラフィー（REVELERIS-Grace ４０ｇ、シリカゲル：２３０〜４００メッシュ、ＡｃＯＥｔ−石油エーテル１：０→１．５：８．５）により精製して、Ｎ^１−（４−（トリフルオロメチル）ピリミジン−２−イル）ベンゼン−１，３−ジアミンに対応する１ｇ（収率２１％）の淡褐色の固体を得た。
；ES+) C₁₁H₉F₃N₄, 計算値 254; 実測値 255 [M+H], HPLC/MS 方法４。 N ¹ - (4- (trifluoromethyl) pyrimidin-2-yl) benzene-1,3-diamine, synthesis of intermediate 540-Me-I-1

Stirring solution of benzene-1,3-diamine (2.0 g, 18.51 mmol) and 2-chloro-4- (trifluoromethyl) pyrimidine (3.4 g, 18.51 mmol) in a 10% ethanol aqueous solution at 0 ° C. Add a concentrated aqueous HCl solution (1.1 ml) to the solution. Next, the obtained mixed solution was stirred at 100 ° C. for 2 hours. Next, the solvent was distilled off, the obtained residue was diluted with cold water, basicized with 10% NaHCO ₃ , and extracted with AcOEt (2 × 50 ml). The combined organic layers were washed with saline (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a crude compound, which was subjected to flash chromatography (REVELERIS-Grace 40 g, silica gel). : 230-400 mesh, AcOEt-petroleum ether 1: 0 → 1.5: 8.5) to ^give, N 1 - (4- (trifluoromethyl) pyrimidin-2-yl) benzene-1,3 A light brown solid of 1 g (yield 21%) corresponding to the diamine was obtained.
ES +) C ₁₁ H ₉ F ₃ N ₄ , Calculated value 254; Measured value 255 [M + H], HPLC / MS Method 4.

ＴＨＦ（１０ｍｌ）中の２，４−ジクロロ−３−メチルキノリン（０．１ｇ、０．４７ｍｍｏｌ）のアルゴンガス下の溶液に、Ｎ^１−（４−（トリフルオロメチル）ピリミジン−２−イル）ベンゼン−１，３−ジアミン（０．１８ｇ、０．７０ｍｍｏｌ）及びｔ−ＢｕＯＮａ（０．１３ｇ、９６．１ｍｍｏｌ）を加えた。得られた反応混合液をアルゴンガスで１０分間脱気し、次にキサントホス（２７ｍｇ、０．０４７ｍｍｏｌ）及びＰｄ（ＯＡｃ）_２（６ｍｇ、０．０２３ｍｍｏｌ）を加え、反応混合液を８０℃で３時間撹拌した。次に、反応混合液を室温に冷却し、冷水（１０ｍｌ）で希釈し、ＡｃＯＥｔ（２×２０ｍｌ）で抽出した。合わせた有機層を食塩水（１０ｍｌ）で洗浄し、Ｎａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して褐色の油状物を得て、（REVELERS Grace、４０ｇ、シリカゲル：２３０〜４００メッシュ、ＡｃＯＥｔ−石油エーテル；１：９→２：８）により精製して、２−［３−（４−トリフルオロメチルピリミジン−２−イルアミノ）フェニルアミノ］−３−メチル−４−クロロキノリンに対応する１ｇ（収率２０％の淡褐色固体を得た。
質量：(ES+) C₂₁H₁₅ClF₃N₅ 計算値 429.10; 実測値 430 [M+H], HPLC/MS 方法４。 Synthesis of 2- [3- (4-trifluoromethylpyrimidine-2-ylamino) phenylamino] -3-methyl-4-chloroquinoline, intermediate 540-Me-I-2

THF 2,4-dichloro-3-methylquinoline (0.1 g, 0.47 mmol) in (10ml) was added under argon ^gas, N 1 - (4- (trifluoromethyl) pyrimidin-2-yl) Benzene-1,3-diamine (0.18 g, 0.70 mmol) and t-BuONa (0.13 g, 96.1 mmol) were added. The obtained reaction mixture was degassed with argon gas for 10 minutes, then xantphos (27 mg, 0.047 mmol) and Pd (OAc) ₂ (6 mg, 0.023 mmol) were added, and the reaction mixture was mixed at 80 ° C. for 3 Stir for hours. The reaction mixture was then cooled to room temperature, diluted with cold water (10 ml) and extracted with AcOEt (2 x 20 ml). The combined organic layers were washed with saline (10 ml), dried in Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a brown oil (REVELERS Grace, 40 g, silica gel: 230-400). Mesh, AcOEt-petroleum ether; purified by 1: 9 → 2: 8) to 2- [3- (4-trifluoromethylpyrimidine-2-ylamino) phenylamino] -3-methyl-4-chloroquinoline. The corresponding 1 g (20% yield) light brown solid was obtained.
Mass: (ES +) C ₂₁ H ₁₅ ClF ₃ N ₅ Calculated value 429.10; Measured value 430 [M + H], HPLC / MS Method 4.

３ｍｌのＮＭＰ中の２−［３−（４−トリフルオロメチルピリミジン−２−イルアミノ）フェニルアミノ］−３−メチル−４−クロロキノリン（０．３ｇ、０．５９８ｍｍｏｌ）の溶液に、４−（ｔｅｒｔ−ブチルアミノ）−ピペリジン（０．５５ｇ、３．４９ｍｍｏｌ）を加え、混合液をマイクロ波オーブン中で２４０℃で４時間加熱した。次に、反応混合液を氷水で冷却、希釈し、濾過した。次に、集めた固体を分取ＨＰＬＣにより精製して、２−［３−（４−トリフルオロメチルピリミジン−２−イルアミノ）フェニルアミノ］−３−メチル−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリンに対応する６０ｍｇ（収率１５％）の淡黄色固体を得た。
質量：（ＥＳ ＋）Ｃ３０ Ｈ ３４ Ｆ ３Ｎ ７、必要５４９．２８；実測値(ES+) C₃₀H₃₄F₃N₇, 計算値 549.28; 実測値 550 [M +H], HPLC/MS 方法５。 The free base of compound 540-Me, 2- [3- (4-trifluoromethylpyrimidine-2-ylamino) phenylamino] -3-methyl-4- (4-tert-butylaminopiperidine-1-yl) quinoline. Synthetic

In a solution of 2- [3- (4-trifluoromethylpyrimidine-2-ylamino) phenylamino] -3-methyl-4-chloroquinoline (0.3 g, 0.598 mmol) in 3 ml of NMP, 4-( tert-Butylamino) -piperidine (0.55 g, 3.49 mmol) was added and the mixture was heated in a microwave oven at 240 ° C. for 4 hours. Next, the reaction mixture was cooled with ice water, diluted, and filtered. The collected solids are then purified by preparative HPLC to 2- [3- (4-trifluoromethylpyrimidine-2-ylamino) phenylamino] -3-methyl-4- (4-tert-butylaminopiperidine). A pale yellow solid of 60 mg (15% yield) corresponding to -1-yl) quinoline was obtained.
Mass: (ES +) C30 H 34 F 3N 7, required 549.28; measured value (ES +) C ₃₀ H ₃₄ F ₃ N ₇ , calculated value 549.28; measured value 550 [M + H], HPLC / MS method 5 ..

０℃で２ｍｌのエタノール中の２−［３−（４−トリフルオロメチルピリミジン−２−イルアミノ）フェニルアミノ］−３−メチル−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリン（０．０５ｇ、０．０９１ｍｍｏｌ）の溶液に、エタノール（２ｍｌ）中の７．２Ｍ ＨＣｌを加え、得られた混合液を室温で１時間撹拌した。反応混合液を減圧下で濃縮し、ジエチルエーテルで洗浄して、２−［３−（４−トリフルオロメチルピリミジン−２−イルアミノ）フェニルアミノ］−３−メチル−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリン塩酸塩に対応する４０ｍｇ（収率７５％）の淡黄色固体を得た。
質量：(ES+) C₃₀H₃₅ClF₃N₇ 計算値 549 (M-HCl) ; 実測値 550 [(M-HCl + H)]⁺, HPLC/MS 方法４。 Compound 540-Me: Synthesis of 2- [3- (4-trifluoromethylpyrimidine-2-ylamino) phenylamino] -3-methyl-4- (4-tert-butylaminopiperidine-1-yl) quinoline hydrochloride

2- [3- (4-Trifluoromethylpyrimidine-2-ylamino) phenylamino] -3-methyl-4- (4-tert-butylaminopiperidine-1-yl) quinoline in 2 ml of ethanol at 0 ° C. 7.2M HCl in ethanol (2 ml) was added to a solution of 0.05 g, 0.091 mmol) and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture is concentrated under reduced pressure, washed with diethyl ether and 2- [3- (4-trifluoromethylpyrimidine-2-ylamino) phenylamino] -3-methyl-4- (4-tert-butyl). A pale yellow solid of 40 mg (75% yield) corresponding to aminopiperidin-1-yl) quinoline hydrochloride was obtained.
Mass: (ES +) C ₃₀ H ₃₅ ClF ₃ N ₇ Calculated value 549 (M-HCl); Measured value 550 [(M-HCl + H)] ⁺ , HPLC / MS Method 4.

Preparation of Compounds 352-CN, 2- (4-Chlorobenzylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline hydrochloride

アセトニトリル（７０ｍｌ）中の２，４−ジクロロキノリン−３−カルボニトリル（０．６ｇ、２．７０２ｍｍｏｌ）の撹拌溶液に、４−（ｔｅｒｔ−ブチルアミノ）ピペリジン（０．４２ｇ、２．７０２ｍｍｏｌ）を加え、反応物を７０℃で１時間撹拌した。次に、反応混合液を室温に冷却した。反応混合液を減圧下で濃縮し、ジエチルエーテルで洗浄して、２−クロロ−３−シアノ−４−［４−（ｔｅｒｔ−ブチルアミノ）ピペリジン−１−イル］−キノリンに対応する６００ｍｇ（収率６５％）のオフホワイトの固体を得た。
質量：(ES+) C₁₉H₂₃ClN₄ 計算値 342.16; 実測値 343 [M+H], HPLC/MS 方法４。 Preparation of Intermediate 2-Chloro-3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline, Intermediate 352-CN-I-1

To a stirred solution of 2,4-dichloroquinoline-3-carbonitrile (0.6 g, 2.702 mmol) in acetonitrile (70 ml), add 4- (tert-butylamino) piperidine (0.42 g, 2.702 mmol). In addition, the reaction was stirred at 70 ° C. for 1 hour. Next, the reaction mixture was cooled to room temperature. The reaction mixture is concentrated under reduced pressure, washed with diethyl ether and 600 mg (yield) corresponding to 2-chloro-3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] -quinoline. An off-white solid with a rate of 65%) was obtained.
Mass: (ES +) C ₁₉ H ₂₃ ClN ₄ Calculated value 342.16; Measured value 343 [M + H], HPLC / MS Method 4.

ＴＨＦ（４ｍｌ）中の２−クロロ−３−シアノ−４−［４−（ｔｅｒｔ−ブチルアミノ）ピペリジン−１−イル］キノリン（０．２ｇ、０．５８５ｍｍｏｌ）の窒素ガス下の溶液に、４−クロロベンジルアミン（０．１２４ｇ、０．８７７ｍｍｏｌ）及びｔ−ＢｕＯＮａ（０．１７０ｇ、１．７５４ｍｍｏｌ）を加えた。得られた混合液をＡｒガスで３０分間脱気した後、キサントホス（３３．８ｍｇ、０．０５８４ｍｍｏｌ）及び酢酸パラジウム（１３ｍｇ、０．０５８４ｍｍｏｌ）を加え、得られた反応混合液を１００℃で３時間撹拌した。反応混合液を室温に冷却し、濾過し、減圧下で濃縮した。残留物を食塩水とＡｃＯＥｔに分配し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、褐色の油状物を得た。粗化合物を、フラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＡｃＯＥｔ−石油エーテル；１０：９０→１５：８５）により精製して、２−（４−クロロベンジルアミノ）−３−シアノ−４−［４−（ｔ−ブチルアミノ）ピペリジン−１−イル］キノリンに対応する６０ｍｇ（収率２２％）の白色固体を得た。
質量：(ES+) C₂₆H₃₀ClN₅ 計算値 447.2; 実測値 448.22 [M+H], HPLC 方法４。 Synthesis of 2- (4-chlorobenzylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline, a free base of compound 352-CN

In a solution of 2-chloro-3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline (0.2 g, 0.585 mmol) in THF (4 ml) under nitrogen gas, 4 -Chlorobenzylamine (0.124 g, 0.877 mmol) and t-BuONa (0.170 g, 1.754 mmol) were added. After degassing the obtained mixed solution with Ar gas for 30 minutes, xantphos (33.8 mg, 0.0584 mmol) and palladium acetate (13 mg, 0.0584 mmol) were added, and the obtained reaction mixed solution was prepared at 100 ° C. for 3 Stir for hours. The reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned into saline and AcOEt, and the aqueous layer was extracted with AcOEt. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown oil. The crude compound was purified by flash chromatography (silicaline: 100-200 mesh, AcOEt-petroleum ether; 10:90 → 15:85) to 2- (4-chlorobenzylamino) -3-cyano-4-[ A 60 mg (22% yield) white solid corresponding to 4- (t-butylamino) piperidine-1-yl] quinoline was obtained.
Mass: (ES +) C ₂₆ H ₃₀ ClN ₅ Calculated value 447.2; Measured value 448.22 [M + H], HPLC method 4.

２ｍｌのジクロロメタン中の２−（４−クロロベンジルアミノ）−３−シアノ−４−［４−（ｔｅｒｔ−ブチルアミノ）ピペリジン−１−イル］キノリン（６０ｍｇ、１０３ｍｍｏｌ）の溶液に、ジエチルエーテル（２．０ｍｌ）中の２Ｍ ＨＣｌの溶液を加え、混合液を室温で３０分間撹拌した。反応混合液を減圧下で濃縮し、ジエチルエーテルで洗浄して、２−（４−クロロベンジルアミノ）−３−シアノ−４−［４−（ｔｅｒｔ−ブチルアミノ）ピペリジン−１−イル］キノリン塩酸塩に対応する５５ｍｈ（収率７８％）のオフホワイトの固体を得た。
質量：(ES+) C₂₆H₃₁Cl₂N₅ 計算値 483 ; 実測値 446 [M-HCl-H], HPLC 方法４。 Synthesis of Compounds 352-CN, 2- (4-Chlorobenzylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline hydrochloride

Diethyl ether (2) in a solution of 2- (4-chlorobenzylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline (60 mg, 103 mmol) in 2 ml of dichloromethane. A solution of 2M HCl in (0.0 ml) was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture is concentrated under reduced pressure, washed with diethyl ether, and 2- (4-chlorobenzylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline hydrochloride. An off-white solid of 55 mh (78% yield) corresponding to the salt was obtained.
Mass: (ES +) C ₂₆ H ₃₁ Cl ₂ N ₅ Calculated 483; Measured 446 [M-HCl-H], HPLC Method 4.

Compounds 498-CN, 2- [4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) -3-methylbenzylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1) -Il) Preparation of quinoline hydrochloride

ＴＨＦ（１０ｍｌ）中の２−クロロ−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリン、中間体３５２−ＣＮ−Ｉ−１（５００ｍｇ、１．４６ｍｍｏｌ）の窒素ガス下の溶液に、３−メチル−４−ブロモベンジルアミン塩酸塩（３７７ｍｇ、１．６０８ｍｍｏｌ）及びｔ−ＢｕＯＮａ（２８０ｍｇ、２．９２２ｍｍｏｌ）を加えた。得られた混合液をアルゴンガスで１０分間脱気し、次にキサントホス（８４ｍｇ、０．１４６１ｍｍｏｌ）及びＰｄ（ＯＡｃ）_２（１６ｍｇ、０．０７３ｍｍｏｌ）を加え、反応混合液を還流下で３時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、減圧下で濃縮した。次に、残留物を食塩水とＥｔＯＡｃに分配し、水層をＥｔＯＡｃで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、褐色油状物を得た。粗化合物をフラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＥｔＯＡｃ−石油エーテル；４０：６０→１００：０）により精製して、２−（３−メチル−４−ブロモベンジルアミノ）−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリンに対応する２００ｍｇ（収率２７％）のオフホワイトの固体を得た。
質量：(ES+) C₂₇H₃₂BrN₅ 計算値 505; 実測値 506 [M+H], HPLC/MS 方法２。 Synthesis of 2- (3-Methyl-4-bromobenzylamino) -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline, intermediate 498-CN-I-1

Nitrogen gas of 2-chloro-3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline, intermediate 352-CN-I-1 (500 mg, 1.46 mmol) in THF (10 ml) To the solution below was added 3-methyl-4-bromobenzylamine hydrochloride (377 mg, 1.608 mmol) and t-BuONa (280 mg, 2.922 mmol). The obtained mixture was degassed with argon gas for 10 minutes, then xantphos (84 mg, 0.1461 mmol) and Pd (OAc) ₂ (16 mg, 0.073 mmol) were added, and the reaction mixture was refluxed for 3 hours. Stirred. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was then partitioned between saline and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown oil. The crude compound was purified by flash chromatography (silicaline: 100-200 mesh, EtOAc-petroleum ether; 40:60 → 100: 0) and 2- (3-methyl-4-bromobenzylamino) -3-cyano-. A 200 mg (27% yield) off-white solid corresponding to 4- (4-tert-butylaminopiperidine-1-yl) quinoline was obtained.
Mass: (ES +) C ₂₇ H ₃₂ BrN ₅ Calculated value 505; Measured value 506 [M + H], HPLC / MS Method 2.

トルエン（１０ｍｌ）中の２−（３−メチル−４−ブロモベンジルアミノ）−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリン（１９０ｍｇ、０．３７６ｍｍｏｌ）の窒素ガス下の溶液に、４−（ピリジン−３−イル）ピリミジン−２−アミン（７１ｍｇ、０．４１３ｍｍｏｌ）及びｔ−ＢｕＯＮａ（７２ｍｇ、０．７５２ｍｍｏｌ）を加えた。得られた混合液をアルゴンガスで１０分間脱気し、次にキサントホス（２１ｍｇ、０．０３７６ｍｍｏｌ）及びＰｄ_２（ｄｂａ）_３（３４ｍｇ、０．０３７６ｍｍｏｌ）を加え、反応混合液を１００℃で１時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、減圧下で濃縮した。残留物を食塩水とＥｔＯＡｃに分配し、水層をＥｔＯＡｃで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して黄色油状物を得た。粗化合物を、フラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＭｅＯＨ−ＣＨＣｌ_３；０：１００→２０：８０）により精製して、２−［４−（４−（ピリジン−３−イル）ピリミジン−２−イルアミノ）−３−メチルベンジルアミノ］−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリンに対応する６０ｍｇ（収率２０％）の淡黄色固体を得た。
質量：(ES+) C₃₆H₃₉N₉ 計算値 597; 実測値 598 [M+H], HPLC/MS 方法６。 Free base of compound 498-CN, 2- [4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) -3-methylbenzylamino] -3-cyano-4- (4-tert-butylamino) Piperidine-1-yl) Synthesis of quinoline

Nitrogen gas of 2- (3-methyl-4-bromobenzylamino) -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline (190 mg, 0.376 mmol) in toluene (10 ml) To the solution below was added 4- (pyridin-3-yl) pyrimidin-2-amine (71 mg, 0.413 mmol) and t-BuONa (72 mg, 0.752 mmol). The obtained mixture is degassed with argon gas for 10 minutes, then xantphos (21 mg, 0.0376 mmol) and Pd ₂ (dba) ₃ (34 mg, 0.0376 mmol) are added, and the reaction mixture is mixed at 100 ° C. 1 Stir for hours. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned between saline and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a yellow oil. The crude compound was purified by flash chromatography (silicaline: 100-200 mesh, MeOH-CHCl ₃ ; 0: 100 → 20: 80) and 2- [4- (4- (pyridin-3-yl) pyrimidin-). 2-Ilamino) -3-methylbenzylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline was obtained in an amount of 60 mg (20% yield) of a pale yellow solid.
Mass: (ES +) C ₃₆ H ₃₉ N ₉ Calculated value 597; Measured value 598 [M + H], HPLC / MS Method 6.

ＥｔＯＨ（０．５ｍｌ）中の２−［４−（４−（ピリジン−３−イル）ピリミジン−２−イルアミノ）−３−メチルベンジルアミノ］−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリン（０．０６ｇ、０．１００ｍｍｏｌ）の溶液に、ＥｔＯＨ（０．５ｍｌ）中の７．２Ｍ ＨＣｌを加え、混合液を室温で１時間撹拌した。反応混合液を減圧下で濃縮し、ジエチルエーテルで洗浄して、２−［４−（４−（ピリジン−３−イル）ピリミジン−２−イルアミノ）−３−メチルベンジルアミノ］−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリン塩酸塩に対応する５５ｍｇ（収率８７％）の淡黄色固体を得た。
質量：( ES+) C₃₆H₄₀N₉Cl 計算値 597 (M-HCl) ; 実測値 598[M +H], 方法４。 Compounds 498-CN, 2- [4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) -3-methylbenzylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1) -Il) Synthesis of quinoline hydrochloride

2- [4- (4- (Pyridine-3-yl) pyrimidin-2-ylamino) -3-methylbenzylamino] -3-cyano-4- (4-tert-butylamino) in EtOH (0.5 ml) To a solution of piperidine-1-yl) quinoline (0.06 g, 0.100 mmol) was added 7.2 M HCl in EtOH (0.5 ml) and the mixture was stirred at room temperature for 1 hour. The reaction mixture is concentrated under reduced pressure, washed with diethyl ether, and 2- [4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) -3-methylbenzylamino] -3-cyano-. A pale yellow solid of 55 mg (87% yield) corresponding to 4- (4-tert-butylaminopiperidine-1-yl) quinoline hydrochloride was obtained.
Mass: (ES +) C ₃₆ H ₄₀ N ₉ Cl Calculated value 597 (M-HCl); Measured value 598 [M + H], Method 4.

Compound of Example 500-CN, 4- (4- (tert-butylamino) piperidine-1-yl) -2- (3-methyl-3-cyano-4- (4-methylpyrimidine-2-ylamino) phenyl Preparation of amino) quinoline hydrochloride

室温で丸底フラスコ中で、ＤＭＦ（１５ｍｌ）中の２−フルオロ−５−ニトロトルエン（１．０ｇ、６．４５１ｍｍｏｌ）の撹拌溶液に、２−アミノ−４−メチルピリミジン（０．７７ｇ、６．４５１ｍｍｏｌ）及びＣｓ_２ＣＯ_３（２．４１ｇ、９．６７７ｍｍｏｌ）を加え、８０℃で１６時間撹拌した。反応をＴＬＣ（３０％酢酸エチル／石油エーテル）で追跡した。反応の完了後、反応物質を室温にし、氷水に注ぎ、ＡｃＯＥｔ（２×２５ｍｌ）で抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、粗４−メチル−Ｎ−（２−メチル−４−ニトロフェニル）ピリミジン−２−アミン（２．３ｇ）を得た。我々は、精製することなく直接次の工程に進んだ。
質量：(ES+) C₁₂H₁₂N₄O₂ 計算値 244; 実測値 245.1 [M+H], HPLC/MS 方法７。 Synthesis of 4-methyl-N- (2-methyl-4-nitrophenyl) pyrimidin-2-amine, intermediate 500-CN-I-1

In a round bottom flask at room temperature, 2-amino-4-methylpyrimidine (0.77 g, 6.451 mmol) to a stirred solution of 2-fluoro-5-nitrotoluene (1.0 g, 6.451 mmol) in DMF (15 ml). 451 mmol) and Cs ₂ CO ₃ (2.41 g, 9.677 mmol) were added, and the mixture was stirred at 80 ° C. for 16 hours. The reaction was followed by TLC (30% ethyl acetate / petroleum ether). After completion of the reaction, the reactants were brought to room temperature, poured into ice water and extracted with AcOEt (2 x 25 ml). The combined organic layers are _{dried over Na 2} SO ₄ , filtered, concentrated under reduced pressure and crude 4-methyl-N- (2-methyl-4-nitrophenyl) pyrimidin-2-amine (2.3 g). Got We proceeded directly to the next step without purification.
Mass: (ES +) C ₁₂ H ₁₂ N ₄ O ₂ Calculated value 244; Measured value 245.1 [M + H], HPLC / MS Method 7.

１０％Ｐｄ−Ｃ（１００ｍｇ）をエタノール中の化合物５００−ＣＮ−Ｉ−１（２．３ｇ、９．３８７ｍｍｏｌ）の撹拌溶液に室温で加えた。反応混合液を水素下（５０ｐｓｉ）室温で５時間攪拌した。反応混合液を濾過し、減圧下で濃縮して褐色油状物を得た。粗化合物をエーテルで洗浄し、２−メチル−Ｎ^１−（４−メチルピリミジン−２−イル）ベンゼン−１，４−ジアミンに対応する５００ｍｇ（２工程で収率２３％）の褐色固体を得た。
質量：(ES+) C₁₂H₁₄N₄ 計算値 214.12; 実測値 215.2 [M+H], HPLC/MS 方法４。 Synthesis of 2-methyl-N ^1- (4-methylpyrimidine-2-yl) benzene-1,4-diamine, intermediate 500-CN-I-2

10% Pd-C (100 mg) was added to a stirred solution of compound 500-CN-I-1 (2.3 g, 9.387 mmol) in ethanol at room temperature. The reaction mixture was stirred under hydrogen (50 psi) at room temperature for 5 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a brown oil. The crude compound was washed with ether to give a brown solid of 500 mg (23% yield in 2 steps) corresponding to 2-methyl ^{-N-1- (4-methylpyrimidine-2-yl) benzene-1,4-diamine.} rice field.
Mass: (ES +) C ₁₂ H ₁₄ N ₄ Calculated value 214.12; Measured value 215.2 [M + H], HPLC / MS Method 4.

ＴＨＦ（２０ｍｌ）中の化合物５００−ＣＮ−Ｉ−２（０．２２０ｇ、０．９６４ｍｍｏｌ）の窒素ガス下の溶液に、２−クロロ−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリン、３５２−ＣＮ−Ｉ−１（０．３ｇ、０．８７７ｍｍｏｌ）及びｔ−ＢｕＯＮａ（０．１６８ｇ、１．７５４ｍｍｏｌ）加えた。得られた混合液をアルゴンガスで３０分間脱気し、次にキサントホス（５０ｍｇ、０．０８７ｍｍｏｌ）及びＰｄ（ＯＡｃ）_２（１０ｍｇ、０．０４３ｍｍｏｌ）を加え、反応混合液を８０℃で３時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、減圧下で濃縮した。残留物を食塩水とＡｃＯＥｔに分配し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、褐色油状物を得た。粗化合物を、フラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、１０％ＭｅＯＨ：ＤＣＭ）により精製して、２−［４−（４−メチル−２−ピリミジンアミノ）−３−メチル−フェニルアミノ］−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）−キノリンに対応する５０ｍｇ（収率１０．９％）の白色固体を得た。
質量：(ES+) C₃₁H₃₆N₈ 計算値 520.31; 実測値 521.3 [M+H], 方法４。 Free base of compound 500-CN, 2- [4- (4-Methyl-2-pyrimidineamino) -3-methyl-phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) ) -Synthesis of quinoline

2-Chloro-3-cyano-4- (4-tert-butylaminopiperidin-) in a solution of compound 500-CN-I-2 (0.220 g, 0.964 mmol) in THF (20 ml) under nitrogen gas. 1-Il) quinoline, 352-CN-I-1 (0.3 g, 0.877 mmol) and t-BuONa (0.168 g, 1.754 mmol) were added. The obtained mixture is degassed with argon gas for 30 minutes, then xantphos (50 mg, 0.087 mmol) and Pd (OAc) ₂ (10 mg, 0.043 mmol) are added, and the reaction mixture is heated at 80 ° C. for 3 hours. Stirred. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned into saline and AcOEt, and the aqueous layer was extracted with AcOEt. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown oil. The crude compound is purified by flash chromatography (silicaline: 100-200 mesh, 10% MeOH: DCM) and 2- [4- (4-methyl-2-pyrimidineamino) -3-methyl-phenylamino]-. A 50 mg (10.9% yield) white solid corresponding to 3-cyano-4- (4-tert-butylaminopiperidine-1-yl) -quinoline was obtained.
Mass: (ES +) C ₃₁ H ₃₆ N ₈ Calculated 520.31; Measured 521.3 [M + H], Method 4.

１ｍｌのジクロロメタン中の２−［４−（４−メチル−２−ピリミジンアミノ）−３−メチル−フェニルアミノ］−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）−キノリン（５０ｍｇ、０．０５９ｍｍｏｌ）の溶液に、ジエチルエーテル（１．０ｍｌ）中の２Ｍ ＨＣｌを加え、混合液を室温で３０分間撹拌した。反応混合液を減圧下で濃縮し、ジエチルエーテルで洗浄して、２−［４−（４−メチル−２−ピリミジンアミノ）−３−メチル−フェニルアミノ］−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）−キノリン塩酸塩に対応する４１ｍｇ（収率７５％）のオフホワイトの固体を得た。
質量：(ES+) C₃₁H₃₇ClN₈ 計算値 555.1; 実測値 521.1 [M-HCl+H], HPLC/MS 方法２。 Compounds 500-CN, 2- [4- (4-Methyl-2-pyrimidineamino) -3-methyl-phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) -quinoline Synthesis of hydrochloride

2- [4- (4-Methyl-2-pyrimidineamino) -3-methyl-phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) -quinolin in 1 ml of dichloromethane To a solution of (50 mg, 0.059 mmol) was added 2M HCl in diethyl ether (1.0 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture is concentrated under reduced pressure, washed with diethyl ether, and 2- [4- (4-methyl-2-pyrimidineamino) -3-methyl-phenylamino] -3-cyano-4- (4-). A 41 mg (75% yield) off-white solid corresponding to tert-butylaminopiperidine-1-yl) -quinoline hydrochloride was obtained.
Mass: (ES +) C ₃₁ H ₃₇ ClN ₈ Calculated 555.1; Measured 521.1 [M-HCl + H], HPLC / MS Method 2.

Compound of Example 502-CN, 2- [4- (4,6-dimethyl-2-pyrimidineamino) -3-methyl-phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1) -Il) -Preparation of quinoline hydrochloride

室温でフラスコ中で、ＤＭＦ（１５ｍｌ）中の２−フルオロ−５−ニトロトルエン（２ｇ、１２．９０３ｍｍｏｌ）の撹拌溶液に、２−アミノ−３，５−ジメチルピリミジン（１．５８ｇ、１２．９０ｍｍｏｌ）及びＣｓ_２ＣＯ_３（６．２ｇ、２５．８０６ｍｍｏｌ）を室温で添加し、８０℃で１６時間撹拌した。反応混合液をＴＬＣ（５０％酢酸エチル／石油エーテル）で追跡した。反応の完了後、反応物を室温にし、氷水に注ぎ、混合液をＡｃＯＥｔ（２×１００ｍｌ）で抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、粗４−メチル−Ｎ−（２−メチル−４−ニトロフェニル）ピリミジン−２−アミン（２．２ｇ）を得た。粗生成物を、精製することなく次の工程に使用した。
質量：(ES+) C₁₃H₁₄N₄O₂ 計算値 258.1; 実測値 259.1 [M+H], HPLC/MS 方法２。 Synthesis of 4,6-dimethyl-N- (2-methyl-4-nitrophenyl) pyrimidin-2-amine, intermediate 502-CN-I-1

2-Amino-3,5-dimethylpyrimidine (1.58 g, 12.90 mmol) in a stirred solution of 2-fluoro-5-nitrotoluene (2 g, 12.903 mmol) in DMF (15 ml) in a flask at room temperature. And Cs ₂ CO ₃ (6.2 g, 25.806 mmol) were added at room temperature and stirred at 80 ° C. for 16 hours. The reaction mixture was followed by TLC (50% ethyl acetate / petroleum ether). After completion of the reaction, the reaction was brought to room temperature, poured into ice water and the mixture was extracted with AcOEt (2 x 100 ml). The combined organic layers were _{dried over Na 2} SO ₄ , filtered, concentrated under reduced pressure and crude 4-methyl-N- (2-methyl-4-nitrophenyl) pyrimidin-2-amine (2.2 g). Got The crude product was used in the next step without purification.
Mass: (ES +) C ₁₃ H ₁₄ N ₄ O ₂ Calculated value 258.1; Measured value 259.1 [M + H], HPLC / MS Method 2.

エタノール中の化合物５０２−ＣＮ−Ｉ−１（２．２ｇ、８．５２３ｍｍｏｌ）の撹拌溶液に、室温で１０％Ｐｄ−Ｃ（１００ｍｇ）を加えた。反応混合液を水素下（５０ｐｓｉ）、室温で５時間攪拌した。次に、反応混合液を濾過し、減圧下で濃縮して、褐色油状物を得た。粗化合物を、フラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、２％ＭｅＯＨ：ＤＣＭ）により精製して、２−メチル−Ｎ^１−（４−メチルピリミジン−２−イル）ベンゼン−１，４−ジアミンに対応する５００ｍｇ（２工程で収率１６％）の褐色固体を得た。
質量：(ES+) C₁₃H₁₆N₄ 計算値 228.14; 実測値 229.2 [M+H], HPLC/MS 方法７。 N ¹ - (4,6-dimethyl-pyrimidin-2-yl) -2-methylbenzene-1,4-diamine, synthesis of intermediate 502-CN-I-2

To a stirred solution of compound 502-CN-I-1 (2.2 g, 8.523 mmol) in ethanol was added 10% Pd-C (100 mg) at room temperature. The reaction mixture was stirred under hydrogen (50 psi) at room temperature for 5 hours. The reaction mixture was then filtered and concentrated under reduced pressure to give a brown oil. The crude compound is purified by flash chromatography (silica gel: 100-200 mesh, 2% MeOH: DCM) to 2-methyl-N- ^1- (4-methylpyrimidine-2-yl) benzene-1,4-diamine. A brown solid of 500 mg (yield 16% in 2 steps) corresponding to the above was obtained.
Mass: (ES +) C ₁₃ H ₁₆ N ₄ Calculated value 228.14; Measured value 229.2 [M + H], HPLC / MS Method 7.

ＴＨＦ（２０ｍｌ）中の化合物５０２−ＣＮ−Ｉ−２（０．１９９ｇ、０．８７７ｍｍｏｌ）の窒素ガス下の溶液に、２−クロロ−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリン、中間体３５２−ＣＮ−Ｉ−１（０．３ｇ、０．８７７ｍｍｏｌ）及びｔ−ＢｕＯＮａ（０．１６８ｇ、１．７５４ｍｍｏｌ）を加えた。得られた混合液をアルゴンガスで３０分間脱気し、次にキサントホス（５０ｍｇ、０．０８７ｍｍｏｌ）及びＰｄ（ＯＡｃ）_２（１０ｍｇ、０．０４３ｍｍｏｌ）を加え、反応混合液を８０℃で３時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、減圧下で濃縮した。残留物を食塩水とＡｃＯＥｔに分配し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して褐色油状物を得た。粗化合物を、フラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、１０％ＭｅＯＨ：ＤＣＭ）により精製して、２−［４−（４，６−ジメチル−２−ピリミジンアミノ）−３−メチル−フェニルアミノ］−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）−キノリンに対応する７０ｍｇ（収率１４．５％）の白色固体を得た。
質量：(ES+) C₃₂H₃₈N₈ 計算値 534.32; 実測値 535.3 [M+H], HPLC/MS 方法６。 Free base of compound 502-CN, 2- [4- (4,6-dimethyl-2-pyrimidineamino) -3-methyl-phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1) -Il) -Quinoline synthesis

2-Chloro-3-cyano-4- (4-tert-butylaminopiperidin-) in a solution of compound 502-CN-I-2 (0.199 g, 0.877 mmol) in THF (20 ml) under nitrogen gas. 1-Il) quinoline, intermediate 352-CN-I-1 (0.3 g, 0.877 mmol) and t-BuONa (0.168 g, 1.754 mmol) were added. The obtained mixture is degassed with argon gas for 30 minutes, then xantphos (50 mg, 0.087 mmol) and Pd (OAc) ₂ (10 mg, 0.043 mmol) are added, and the reaction mixture is heated at 80 ° C. for 3 hours. Stirred. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned into saline and AcOEt, and the aqueous layer was extracted with AcOEt. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown oil. The crude compound was purified by flash chromatography (silica gel: 100-200 mesh, 10% MeOH: DCM) and 2- [4- (4,6-dimethyl-2-pyrimidineamino) -3-methyl-phenylamino. ] -3-Cyano-4- (4-tert-butylaminopiperidine-1-yl) -quinoline corresponding to 70 mg (14.5% yield) of white solid was obtained.
Mass: (ES +) C ₃₂ H ₃₈ N ₈ Calculated value 534.32; Measured value 535.3 [M + H], HPLC / MS Method 6.

１ｍｌのＤＣＭ中の化合物２−［４−（４，６−ジメチル−２−ピリミジンアミノ）−３−メチル−フェニルアミノ］−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）−キノリン（７０ｍｇ．１３１ｍｍｏｌ）の溶液に、ジエチルエーテル（１．０ｍｌ）中の２Ｍ ＨＣｌを加え、混合液を室温で３０分間撹拌した。次に、反応混合液を減圧下で濃縮し、ジエチルエーテルで洗浄して、２−［４−（４，６−ジメチル−２−ピリミジンアミノ）−３−メチル−フェニルアミノ］−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）−キノリン塩酸塩に対応する６０ｍｇ（収率８１％）のオフホワイトの固体を得た。
質量：(ES+) C₃₂H₃₉ClN₈ 計算値 569.2; 実測値 535.3 [M-HCl+H], HPLC/MS 方法６。 Compounds 502-CN, 2- [4- (4,6-dimethyl-2-pyrimidineamino) -3-methyl-phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) -Synthesis of quinoline hydrochloride

Compound 2- [4- (4,6-dimethyl-2-pyrimidineamino) -3-methyl-phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) in 1 ml of DCM ) -To a solution of quinoline (70 mg.131 mmol) was added 2M HCl in diethyl ether (1.0 ml) and the mixture was stirred at room temperature for 30 minutes. Next, the reaction mixture is concentrated under reduced pressure, washed with diethyl ether, and 2- [4- (4,6-dimethyl-2-pyrimidineamino) -3-methyl-phenylamino] -3-cyano-. A 60 mg (81% yield) off-white solid corresponding to 4- (4-tert-butylaminopiperidine-1-yl) -quinoline hydrochloride was obtained.
Mass: (ES +) C ₃₂ H ₃₉ ClN ₈ Calculated 569.2; Measured 535.3 [M-HCl + H], HPLC / MS Method 6.

Compound of Example 510-CN, 2- [4- (4-Methyl-6-methoxypyrimidine-2-ylamino) -3-methylphenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-) 1-Il) Preparation of quinoline hydrochloride

濃ＨＣｌ水溶液（５０ｍｌ）中の２−アミノ−４−メトキシ−６−メチルピリミジン（５ｇ、３５．９７ｍｍｏｌ）の溶液に、水（５ｍｌ）中のＮａＮＯ_２（２．９７ｇ、４３．１６ｍｍｏｌ）を０℃で３０分間ゆっくり滴加し、反応混合液を室温で１時間撹拌した。次に、反応混合液を１０Ｎ水酸化ナトリウム溶液でクエンチし、不溶性物質を濾過し、濾液を食塩水とＡｃＯＥｔに分配し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、褐色油状物を得た。粗化合物をフラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＡｃＯＥｔ−石油エーテル；１０：９０→１５：８５）により精製して、２−クロロ−４−メトキシ−６−メチルピリミジンに対応する６００ｍｇ（収率８％）の白色固体を得た。 Synthesis of 2-chloro-4-methoxy-6-methylpyrimidine, intermediate 510-CN-I-1

_{0 NaNO 2} (2.97 g, 43.16 mmol) in water (5 ml) in a solution of 2-amino-4-methoxy-6-methylpyrimidine (5 g, 35.97 mmol) in concentrated HCl aqueous solution (50 ml). The reaction mixture was slowly added dropwise at ° C. for 30 minutes, and the reaction mixture was stirred at room temperature for 1 hour. Next, the reaction mixture was quenched with 10N sodium hydroxide solution, the insoluble material was filtered, the filtrate was partitioned into saline and AcOEt, and the aqueous layer was extracted with AcOEt. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown oil. The crude compound was purified by flash chromatography (silica gel: 100-200 mesh, AcOEt-petroleum ether; 10:90 → 15:85) to 600 mg (yield) corresponding to 2-chloro-4-methoxy-6-methylpyrimidine. A white solid having a rate of 8%) was obtained.

１，４−ジオキサン（１５ｍｌ）中の化合物５１０−ＣＮ−Ｉ−１（６００ｍｇ、３．７９７ｍｍｏｌ）の窒素ガス下の溶液に、化合物３（５７８ｍｇ、３．７９７ｍｍｏｌ）及び炭酸セシウム（２．１４８ｇ、６．５９２ｍｍｏｌ）を加えた。得られた混合液をアルゴンガスで３０分間脱気し、次にキサントホス（４４０ｍｇ、０．７５９ｍｍｏｌ）及びＰｄ_２（ｄｂａ）_３（３４８ｍｇ、０．３７９ｍｍｏｌ）を加え、反応混合液を１００℃で１６時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、減圧下で濃縮した。残留物を食塩水とＡｃＯＥｔに分配し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、褐色油状物を得た。粗化合物を、フラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＡｃＯＥｔ−石油エーテル；７０％）により精製して、４−メトキシ−６−メチル−Ｎ−（２−メチル−５−ニトロフェニル）ピリミジン−２−アミンに対応する０．３ｇ（収率２８．８％）の淡黄色固体を得た。
質量：(ES+) C₁₃H₁₄N₄O₃ 計算値 274.11; 実測値 275.1 [M+H], HPLC/MS 方法８。 Synthesis of 4-methoxy-6-methyl-N- (2-methyl-5-nitrophenyl) pyrimidin-2-amine, intermediate 510-CN-I-2

In a solution of compound 510-CN-I-1 (600 mg, 3.797 mmol) in 1,4-dioxane (15 ml) under nitrogen gas, compound 3 (578 mg, 3.797 mmol) and cesium carbonate (2.148 g, 2.148 g, 6.592 mmol) was added. The obtained mixture was degassed with argon gas for 30 minutes, then xantphos (440 mg, 0.759 mmol) and Pd ₂ (dba) ₃ (348 mg, 0.379 mmol) were added, and the reaction mixture was added at 100 ° C. to 16 Stir for hours. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned into saline and AcOEt, and the aqueous layer was extracted with AcOEt. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown oil. The crude compound was purified by flash chromatography (silica gel: 100-200 mesh, AcOEt-petroleum ether; 70%) to 4-methoxy-6-methyl-N- (2-methyl-5-nitrophenyl) pyrimidine-. A pale yellow solid of 0.3 g (yield 28.8%) corresponding to 2-amine was obtained.
Mass: (ES +) C ₁₃ H ₁₄ N ₄ O ₃ Calculated value 274.11; Measured value 275.1 [M + H], HPLC / MS Method 8.

ＥｔＯＨ（３０ｍｌ）中の化合物５１０−ＣＮ−Ｉ−２（０．３ｇ、１．００６ｍｍｏｌ）の溶液に１０％Ｐｄ／Ｃ（３０ｍｇ）を加えた。得られた混合液を水素下（１バール）で１６時間撹拌した。触媒を濾別し、ＥｔＯＨで洗浄し、溶媒を減圧下で濃縮して、Ｎ^１−（４−メトキシ−６−メチルピリミジン−２−イル）−６−メチルベンゼン−１，３−ジアミンに対応する０．２０ｇの淡褐色固体を得た。粗生成物をさらに精製することなく次の工程で使用した。 N ¹ - (4-methoxy-6-methyl-pyrimidin-2-yl) -6-methyl-1,3-diamine, synthesis of intermediate 510-CN-1-3

10% Pd / C (30 mg) was added to a solution of compound 510-CN-I-2 (0.3 g, 1.006 mmol) in EtOH (30 ml). The resulting mixture was stirred under hydrogen (1 bar) for 16 hours. The catalyst was filtered off, washed with EtOH, the solvent was concentrated under reduced ^pressure, N 1 - corresponding to the (4-methoxy-6-methyl-pyrimidin-2-yl) -6-methyl-1,3-diamine 0.20 g of a light brown solid was obtained. The crude product was used in the next step without further purification.

１，４−ジオキサン（１０ｍｌ）中の化合物５１０−ＣＮ−Ｉ−３（０．２ｇ、０．５８５ｍｍｏｌ）の窒素ガス下の溶液に、２−クロロ−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリン、中間体３５２−ＣＮ−Ｉ−１（０１４２ｇ、０．５８５ｍｍｏｌ）及び炭酸セシウム（３８１ｍｇ、１．１６９ｍｍｏｌ）を加えた。得られた混合液をＡｒガスで３０分間脱気し、次にキサントホス（６８ｍｇ、０．１１６９ｍｍｏｌ）及びＰｄ_２（ｄｂａ）_３（５４ｍｇ、０．０５８５ｍｍｏｌ）を加え、反応混合液を１００℃で４時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、減圧下で濃縮した。残留物を食塩水とＡｃＯＥｔに分配し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、褐色油状物を得た。粗化合物をフラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＡｃＯＥｔ−石油エーテル；１０：９０→１５：８５）により精製して、２−［４−（４−メチル−６−メトキシピリミジン−２−イルアミノ）−３−メチルフェニルアミノ］−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリンに対応する９０ｍｇ（収率２８％）の白色固体を得た。
質量：(ES+) C₃₂H₃₈N₈O 計算値 550.31; 実測値 551.3 [M+H], HPLC/MS 方法８。 Free base of compound 510-CN, 2- [4- (4-Methyl-6-methoxypyrimidine-2-ylamino) -3-methylphenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-) 1-Il) Synthesis of quinoline

In a solution of compound 510-CN-I-3 (0.2 g, 0.585 mmol) in 1,4-dioxane (10 ml) under nitrogen gas, 2-chloro-3-cyano-4- (4-tert-). Butylaminopiperidine-1-yl) quinoline, intermediate 352-CN-I-1 (0142 g, 0.585 mmol) and cesium carbonate (381 mg, 1.169 mmol) were added. The obtained mixture was degassed with Ar gas for 30 minutes, then xantphos (68 _{mg, 0.1169 mmol) and Pd 2} (dba) ₃ (54 mg, 0.0585 mmol) were added, and the reaction mixture was mixed at 100 ° C. 4 Stir for hours. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned into saline and AcOEt, and the aqueous layer was extracted with AcOEt. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown oil. The crude compound was purified by flash chromatography (silicaline: 100-200 mesh, AcOEt-petroleum ether; 10:90 → 15:85) and 2- [4- (4-methyl-6-methoxypyrimidine-2-ylamino). ) -3-Methylphenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline was obtained in 90 mg (28% yield) of a white solid.
Mass: (ES +) C ₃₂ H ₃₈ N ₈ O Calculated value 550.31; Measured value 551.3 [M + H], HPLC / MS Method 8.

２ｍｌの１，４−ジオキサン中の化合物５１０−ＣＮの遊離塩基（９０ｍｇ、０．１６３６ｍｍｏｌ）の溶液に、１，４−ジオキサン（２．０ｍｌ）中の４Ｍ ＨＣｌを加え、混合液を室温で３０分間攪拌した。反応混合液を減圧下で濃縮し、ジエチルエーテルで洗浄して、２−［４−（４−メチル−６−メトキシピリミジン−２−イルアミノ）−３−メチルフェニルアミノ］−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリン塩酸塩に対応する８０ｍｇ（収率８４％）のオフホワイトの固体を得た。
質量：(ES+) C₃₂H₃₉ClN₈O 計算値 586.29; 実測値 551 [M-HCl+H], HPLC/MS 方法６。 Compounds 510-CN, 2- [4- (4-Methyl-6-methoxypyrimidine-2-ylamino) -3-methylphenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) ) Synthesis of quinoline hydrochloride salt

To a solution of the free base (90 mg, 0.1636 mmol) of compound 510-CN in 2 ml of 1,4-dioxane, add 4M HCl in 1,4-dioxane (2.0 ml) and mix 30 at room temperature. Stir for minutes. The reaction mixture is concentrated under reduced pressure, washed with diethyl ether, and 2- [4- (4-methyl-6-methoxypyrimidine-2-ylamino) -3-methylphenylamino] -3-cyano-4- An off-white solid of 80 mg (84% yield) corresponding to the (4-tert-butylaminopiperidine-1-yl) quinoline hydrochloride was obtained.
Mass: (ES +) C ₃₂ H ₃₉ ClN ₈ O Calculated value 586.29; Measured value 551 [M-HCl + H], HPLC / MS Method 6.

Compounds 512-CN, 2- [3-Methyl-4- (4,6-dimethylflo [2,3-d] pyrimidin-2-ylamino) phenylamino] -3-cyano-4- (4-tert-butylamino) Preparation of piperidine-1-yl) quinoline hydrochloride

濃ＨＣｌ水溶液（６ｍｌ）中の４，６−ジメチルフロ［２，３−ｄ］ピリミジン−２−アミンの溶液に、水（１ｍｌ）中のＮａＮＯ_２（０．３８ｇ、５．５２１ｍｍｏｌ）を０℃で１０分間ゆっくり滴加し、反応混合液を室温で３時間撹拌した。反応混合液を１０Ｎ水酸化ナトリウム水溶液でクエンチした後、得られた溶液を濾別し、濾液を食塩水とＡｃＯＥｔに分配し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、褐色油状物を得た。粗化合物をフラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＡｃＯＥｔ−石油エーテル；１０：９０→１５：８５）により精製して、２−クロロ−４，６−ジメチルフロ［２，３−ｄ］ピリミジンに対応する３００ｍｇ（収率４７％）の白色固体を得た。 Synthesis of 2-chloro-4,6-dimethylflo [2,3-d] pyrimidine, intermediate 512-CN-I-1

_{NaNO 2} (0.38 g, 5.521 mmol) in water (1 ml) in a solution of 4,6-dimethylflo [2,3-d] pyrimidin-2-amine in a concentrated HCl aqueous solution (6 ml) at 0 ° C. The reaction mixture was slowly added dropwise for 10 minutes, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with 10N aqueous sodium hydroxide solution, the obtained solution was filtered off, the filtrate was partitioned between saline and AcOEt, and the aqueous layer was extracted with AcOEt. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown oil. The crude compound is purified by flash chromatography (silica gel: 100-200 mesh, AcOEt-petroleum ether; 10:90 → 15:85) to 2-chloro-4,6-dimethylflo [2,3-d] pyrimidine. The corresponding 300 mg (47% yield) of white solid was obtained.

１，４−ジオキサン（１０ｍｌ）中の化合物５１２−ＣＮ−Ｉ−１（３００ｍｇ、１．６４８ｍｍｏｌ）の窒素ガス下の溶液に、２−アミノ−４−ニトロトルエン（１５９ｍｇ、１．６４８ｍｍｏｌ）及び炭酸セシウム（１．０７４ｇ、３．２９６ｍｍｏｌ）を加えた。得られた混合液をアルゴンガスで３０分間脱気し、次にキサントホス（１９１ｍｇ、０．３２９ｍｍｏｌ）及びＰｄ_２（ｄｂａ）_３（１５１ｍｇ、０．１６４８ｍｍｏｌ）を加え、得られた反応混合液を１００℃で４時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、減圧下で濃縮した。残留物を食塩水とＡｃＯＥｔに分配し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、褐色油状物を得た。粗化合物を、フラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＡｃＯＥｔ−石油エーテル；７０％）により精製して、４，６−ジメチル−Ｎ−（２−メチル−５−ニトロフェニル）フロ［２，３−ｄ］ピリミジン−２−アミンに対応する０．３ｇ（収率６１％）の淡黄色固体を得た。
質量：(ES+) C₁₅H₁₄N₄O₃ 計算値 298.11; 実測値 299.1 [M+H], HPLC/MS 方法８。 Synthesis of N- (2-methyl-5-nitrophenyl) -4- (pyridin-3-yl) pyrimidin-2-amine, intermediate 512-CN-I-2

2-Amino-4-nitrotoluene (159 mg, 1.648 mmol) and cesium carbonate in a solution of compound 512-CN-I-1 (300 mg, 1.648 mmol) in 1,4-dioxane (10 ml) under nitrogen gas. (1.074 g, 3.296 mmol) was added. The obtained mixed solution was degassed with argon gas for 30 minutes, then xantphos (191 mg, 0.329 mmol) and Pd ₂ (dba) ₃ (151 mg, 0.1648 mmol) were added, and the obtained reaction mixed solution was added to 100. The mixture was stirred at ° C. for 4 hours. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned into saline and AcOEt, and the aqueous layer was extracted with AcOEt. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown oil. The crude compound was purified by flash chromatography (silica gel: 100-200 mesh, AcOEt-petroleum ether; 70%) to 4,6-dimethyl-N- (2-methyl-5-nitrophenyl) flow [2. 3-d] A pale yellow solid of 0.3 g (yield 61%) corresponding to pyrimidine-2-amine was obtained.
Mass: (ES +) C ₁₅ H ₁₄ N ₄ O ₃ Calculated 298.11; Measured 299.1 [M + H], HPLC / MS Method 8.

ＥｔＯＨ（３０ｍｌ）中の化合物５１２−ＣＮ−Ｉ−２（０．３ｇ、１．００６ｍｍｏｌ）の溶液に１０％Ｐｄ／Ｃ（３０ｍｇ）を加えた。得られた混合液を水素下（１バール）で１６時間撹拌した。触媒を濾別し、ＥｔＯＨで洗浄し、溶媒を減圧下で濃縮して、Ｎ^１−（４，６−ジメチルフロ［２，３−ｄ］ピリミジン−２−イル）−６−メチルベンゼン−１，３−ジアミンに対応する０．２９ｇの淡褐色の固体を得た。粗生成物を、さらに精製することなく次の工程で使用した。 N ¹ - (4,6-Jimechirufuro [2,3-d] pyrimidin-2-yl) -6-methyl-1,3-diamine, synthesis of intermediate 512-CN-I-3

10% Pd / C (30 mg) was added to a solution of compound 512-CN-I-2 (0.3 g, 1.006 mmol) in EtOH (30 ml). The resulting mixture was stirred under hydrogen (1 bar) for 16 hours. The catalyst was filtered off, washed with EtOH, and the solvent concentrated under reduced ^pressure, N 1 - (4,6-Jimechirufuro [2,3-d] pyrimidin-2-yl) -6-methylbenzene-1, A light brown solid of 0.29 g corresponding to 3-diamine was obtained. The crude product was used in the next step without further purification.

１，４−ジオキサン（１０ｍｌ）中の化合物３５２−ＣＮ−Ｉ−１（０．４ｇ、１．１６９ｍｍｏｌ）の窒素ガス下の溶液に、化合物５１２−ＣＮ−Ｉ−３（０．３１３ｇ、１．１６９ｍｍｏｌ）及び炭酸セシウム（０．９５３ｇ、２．８９８ｍｍｏｌ）を加えた。得られた混合液をＡｒガスで３０分間脱気し、次にキサントホス（１３５ｍｇ、０．２３３ｍｍｏｌ）及びＰｄ_２（ｄｂａ）_３（１０７ｍｇ、０．１１６ｍｍｏｌ）を加え、反応混合液を１００℃で１２時間攪拌した。次に、反応混合液を室温に冷却し、濾過し、減圧下で濃縮した。残留物を食塩水とＡｃＯＥｔに分配し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、褐色油状物を得た。粗化合物をフラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＡｃＯＥｔ−石油エーテル；１０：９０→１５：８５）により精製して、２−［３−メチル−４−（４，６−ジメチルフロ［２，３−ｄ］ピリミジン−２−イルアミノ）フェニルアミノ］−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリンに対応する３５０ｍｇ（収率５２％）の白色固体を得た。
質量：(ES+) C₃₄H₃₈N₈O 計算値 574.31; 実測値 575.3 [M+H], HPLC/MS 方法４。 Free base of compound 512-CN, 2- [3-methyl-4- (4,6-dimethylflo [2,3-d] pyrimidin-2-ylamino) phenylamino] -3-cyano-4- (4-tert) -Butylaminopiperidine-1-yl) Synthesis of quinoline

In a solution of compound 352-CN-I-1 (0.4 g, 1.169 mmol) in 1,4-dioxane (10 ml) under nitrogen gas, compound 512-CN-I-3 (0.313 g, 1.69 mmol). 169 mmol) and cesium carbonate (0.953 g, 2.898 mmol) were added. The obtained mixed solution was degassed with Ar gas for 30 minutes, then xantphos (135 mg, 0.233 mmol) and Pd ₂ (dba) ₃ (107 mg, 0.116 mmol) were added, and the reaction mixed solution was added at 100 ° C. to 12 Stirred for hours. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned into saline and AcOEt, and the aqueous layer was extracted with AcOEt. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown oil. The crude compound was purified by flash chromatography (silicaline: 100-200 mesh, AcOEt-petroleum ether; 10:90 → 15:85) and 2- [3-methyl-4- (4,6-dimethylflo] [2]. 3-d] pyrimidin-2-ylamino) phenylamino] -3-cyano-4- (4-tert-butylaminopiperidin-1-yl) quinoline-corresponding to 350 mg (52% yield) of white solid was obtained. ..
Mass: (ES +) C ₃₄ H ₃₈ N ₈ O Calculated value 574.31; Measured value 575.3 [M + H], HPLC / MS Method 4.

１，４−ジオキサン（２．０ｍｌ）中の化合物５１２−ＣＮの遊離塩基（１００ｍｇ、０．１６４ｍｍｏｌ）の溶液に、１，４−ジオキサン（２．０ｍｌ）中の４Ｍ ＨＣｌを加え、混合液を室温で３０分間撹拌した。反応混合液を減圧下で濃縮し、ジエチルエーテルで洗浄して、２−［３−メチル−４−（４，６−ジメチルフロ［２，３−ｄ］ピリミジン−２−イルアミノ）フェニルアミノ］−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリン塩酸塩に対応する３３０ｍｇ（収率８８％）のオフホワイトの固体を得た。
質量：(ES+) C₃₄H₃₉ClN₈O 計算値 610.29; 実測値 575.3 [M-HCl+H], HPLC/MS 方法６。 Compound of Example 512-CN, 2- [3-Methyl-4- (4,6-dimethylflo [2,3-d] pyrimidin-2-ylamino) phenylamino] -3-cyano-4- (4-tert) -Butylaminopiperidine-1-yl) Synthesis of quinoline hydrochloride

Add 4M HCl in 1,4-dioxane (2.0 ml) to a solution of the free base (100 mg, 0.164 mmol) of compound 512-CN in 1,4-dioxane (2.0 ml) to add the mixture. The mixture was stirred at room temperature for 30 minutes. The reaction mixture is concentrated under reduced pressure, washed with diethyl ether, and 2- [3-methyl-4- (4,6-dimethylflo [2,3-d] pyrimidin-2-ylamino) phenylamino] -3. An off-white solid of 330 mg (88% yield) corresponding to −cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline hydrochloride was obtained.
Mass: (ES +) C ₃₄ H ₃₉ ClN ₈ O Calculated value 610.29; Measured value 575.3 [M-HCl + H], HPLC / MS Method 6.

Compounds 522-CN, 2- {3-methyl-4- [2- (pyridin-3-yl) pyrimidin-4-ylamino] phenylamino} -3-cyano-4- (4-tert-butylaminopiperidine-1) -Il) Preparation of quinoline hydrochloride

ＴＨＦ（２００ｍｌ）中の２−ヨード−５−アミノトルエン（１０ｇ、４３．１ｍｍｏｌ）の溶液に、重炭酸ナトリウム（１０．８１ｇ、１２８．７６ｍｍｏｌ）及びＢｏｃ_２Ｏ（１４．０９ｇ、６４．６６ｍｍｏｌ）を加え、反応混合液を５０℃で１２時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、減圧下で濃縮した。残留物を食塩水とＡｃＯＥｔに分配し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、４−ヨード−３−メチルフェニルカルバミン酸Ｎ−ｔｅｒｔ−ブチルに対応する１０ｇ（収率６９％）の褐色固体を得た。粗生成物をさらに精製することなく次の工程で使用した。
質量：(ES+) C₁₂H₁₆INO₂ 計算値 333.02; 実測値 332 [M-H], HPLC/MS 方法４。 Synthesis of N-tert-butyl 3-methyl-4-iodophenylcarbamate, intermediate 522-CN-I-1

_{Sodium bicarbonate (10.81 g, 128.76 mmol) and Boc 2} O (14.09 g, 64.66 mmol) in a solution of 2-iodo-5-aminotoluene (10 g, 43.1 mmol) in THF (200 ml). Was added, and the reaction mixture was stirred at 50 ° C. for 12 hours. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned into saline and AcOEt, and the aqueous layer was extracted with AcOEt. The combined organic layers are _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to a brown color of 10 g (69% yield) corresponding to N-tert-butyl 4-iodo-3-methylphenylcarbamate. Obtained a solid. The crude product was used in the next step without further purification.
Mass: (ES +) C ₁₂ H ₁₆ INO ₂ Calculated 333.02; Measured 332 [MH], HPLC / MS Method 4.

１，４−ジオキサン（８ｍｌ）中の２−（ピリジン−３−イル）−４−アミノピリミジン（０．４ｇ、２．３２５ｍｍｏｌ）の窒素ガス下の溶液に、４−ヨード−３−メチルフェニルカルバミン酸ｔｅｒｔ−ブチル（１．５４８ｇ、４．６５１ｍｍｏｌ）及び炭酸セシウム（２．２７３ｇ、６．９７６ｍｍｏｌ）を加えた。得られた混合液をＡｒガスで３０分間脱気し、次にキサントホス（２７０ｍｇ、０．４６５ｍｍｏｌ）及びＰｄ_２（ｄｂａ）_３（２１３ｍｇ、０．２３３ｍｍｏｌ）を加え、反応混合液を１００℃で１２時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、減圧下で濃縮した。残留物を食塩水とＡｃＯＥｔに分配し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して褐色油状物を得た。粗化合物をフラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＡｃＯＥｔ−石油エーテル；１０：９０→１５：８５）により精製して、３−メチル−４−（２−（ピリジン−３−イル）ピリミジン−４−イルアミノ）フェニルカルバミン酸ｔｅｒｔ−ブチルに対応する４００ｍｇ（収率４５％）の褐色固体を得た。
質量：(ES+) C₂₁H₂₃N₅O₂ 計算値 377; 実測値 378 [M+H], HPLC/MS 方法８。 Synthesis of 3-methyl-4- (2- (pyridin-3-yl) pyrimidin-4-ylamino) tert-butyl phenylcarbamate, intermediate 522-CN-I-2

4-Iodo-3-methylphenylcarbamine in a solution of 2- (pyridin-3-yl) -4-aminopyrimidine (0.4 g, 2.325 mmol) in 1,4-dioxane (8 ml) under nitrogen gas. Tert-Butyl acid (1.548 g, 4.651 mmol) and cesium carbonate (2.273 g, 6.976 mmol) were added. The resulting mixture was degassed with Ar gas for 30 minutes, then xantphos (270 mg, 0.465 mmol) and Pd ₂ (dba) ₃ (213 mg, 0.233 mmol) were added, and the reaction mixture was added at 100 ° C. to 12 Stir for hours. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned into saline and AcOEt, and the aqueous layer was extracted with AcOEt. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown oil. The crude compound was purified by flash chromatography (silica gel: 100-200 mesh, AcOEt-petroleum ether; 10:90 → 15:85) to 3-methyl-4- (2- (pyridin-3-yl) pyrimidin-. A brown solid of 400 mg (45% yield) corresponding to tert-butyl 4-ylamino) phenylcarbamate was obtained.
Mass: (ES +) C ₂₁ H ₂₃ N ₅ O ₂ Calculated value 377; Measured value 378 [M + H], HPLC / MS Method 8.

１，４−ジオキサン（１０ｍｌ）中の化合物３−メチル−４−（２−（ピリジン−３−イル）ピリミジン−４−イルアミノ）フェニルカルバミン酸ｔｅｒｔ−ブチル（４００ｍｇ、１．０６１ｍｍｏｌ）の溶液に、１，４−ジオキサン（１０．０ｍｌ）中の４Ｍ ＨＣｌ溶液を加え、混合液を室温で１時間攪拌した。反応混合液を減圧下で濃縮した。残留物を飽和重炭酸塩溶液とＡｃＯＥｔに分配し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、２−メチル−Ｎ^１−（２−（ピリジン−３−イル）ピリミジン−４−イル）ベンゼン−１，４−ジアミンに対応する２５０ｍｇ（収率８５％）の褐色固体を得た。粗生成物をさらに精製することなく次の工程で使用した。
質量：(ES+) C₁₆H₁₅N₅計算値 277.13; 実測値 278 [M+H], HPLC/MS 方法８。 Synthesis of 2-methyl-N ^1- (2- (pyridin-3-yl) pyrimidin-4-yl) benzene-1,4-diamine, intermediate 522-CN-I-3

In a solution of compound 3-methyl-4- (2- (pyridin-3-yl) pyrimidin-4-ylamino) tert-butyl phenylcarbamate (400 mg, 1.061 mmol) in 1,4-dioxane (10 ml), A 4M HCl solution in 1,4-dioxane (10.0 ml) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between a saturated bicarbonate solution and AcOEt, and the aqueous layer was extracted with AcOEt. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to 2-methyl-N- ^1- (2- (pyridin-3-yl) pyrimidin-4-yl) benzene-1, A 250 mg (85% yield) brown solid corresponding to 4-diamine was obtained. The crude product was used in the next step without further purification.
Mass: (ES +) C ₁₆ H ₁₅ N ₅ Calculated 277.13; Measured 278 [M + H], HPLC / MS Method 8.

１，４−ジオキサン（８ｍｌ）中の化合物３５２−ＣＮ−Ｉ−１（０．４ｇ、１．１６９ｍｍｏｌ）の窒素ガス下の溶液に、２−メチル−Ｎ^１−（２−（ピリジン−３−イル）ピリミジン−４−イル）ベンゼン−１，４−ジアミン（０．３２３ｇ、１．１６９ｍｍｏｌ）及び炭酸セシウム（０．９５ｇ、２．９２３ｍｍｏｌ）を加えた。得られた混合液をＡｒガスで３０分間脱気し、次にキサントホス（６７．６ｍｇ、０．０１１７ｍｍｏｌ）及びＰｄ_２（ｄｂａ）_３（１０７ｍｇ、０．０１１７ｍｍｏｌ）を加え、得られた反応混合液を１００℃で１２時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、減圧下で濃縮した。残留物を食塩水とＡｃＯＥｔに分配し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、褐色油状物を得た。粗化合物をフラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＡｃＯＥｔ−石油エーテル；１０：９０→１５：８５）により精製して、２−｛３−メチル−４−［２−（ピリジン−３−イル）ピリミジン−４−イルアミノ］フェニルアミノ｝−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリンに対応する３００ｍｇ（収率５８％）の白色固体を得た。
質量：(ES+) C₃₅H₃₇N₉ 計算値 583; 実測値 584 [M+H], HPLC/MS 方法４。 Free base of compound 522-CN, 2- {3-methyl-4- [2- (pyridin-3-yl) pyrimidin-4-ylamino] phenylamino} -3-cyano-4- (4-tert-butylamino) Piperidine-1-yl) Synthesis of quinoline

In a solution of compound 352-CN-I-1 (0.4 g, 1.169 mmol) in 1,4-dioxane (8 ml) under nitrogen gas, 2-methyl-N- ^1- (2- (pyridin-3-3)). Ill) Pyrimidine-4-yl) Benzene-1,4-diamine (0.323 g, 1.169 mmol) and cesium carbonate (0.95 g, 2.923 mmol) were added. The obtained mixed solution was degassed with Ar gas for 30 minutes, then xantphos (67.6 mg, 0.0117 mmol) and Pd ₂ (dba) ₃ (107 mg, 0.0117 mmol) were added, and the obtained reaction mixed solution was added. Was stirred at 100 ° C. for 12 hours. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned into saline and AcOEt, and the aqueous layer was extracted with AcOEt. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown oil. The crude compound was purified by flash chromatography (silicaline: 100-200 mesh, AcOEt-petroleum ether; 10:90 → 15:85) and 2- {3-methyl-4- [2- (pyridine-3-yl) ) Pyrimidin-4-ylamino] phenylamino} -3-cyano-4- (4-tert-butylaminopiperidin-1-yl) quinoline corresponding to 300 mg (58% yield) of a white solid was obtained.
Mass: (ES +) C ₃₅ H ₃₇ N ₉ Calculated 583; Measured 584 [M + H], HPLC / MS Method 4.

ＤＣＭ（３ｍｌ）中の２−｛３−メチル−４−［２−（ピリジン−３−イル）ピリミジン−４−イルアミノ］フェニルアミノ｝−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリン（３００ｍｇ、０．５１４ｍｍｏｌ）の溶液に、ジエチルエーテル（３．０ｍｌ）中の２Ｍ ＨＣｌを加え、混合液を室温で３０分間撹拌した。反応混合液を減圧下で濃縮し、ジエチルエーテルで洗浄して、２−｛３−メチル−４−［２−（ピリジン−３−イル）ピリミジン−４−イルアミノ］フェニルアミノ｝−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリン塩酸塩に対応する２３０ｍｇ（収率７２％）のオフホワイトの固体を得た。
質量：ES+) C₃₅H₃₈ClN₉ 計算値 619.29; 実測値 584.3[M-HCl+H], HPLC/MS 方法６。 Compounds 522-CN, 2- {3-methyl-4- [2- (pyridin-3-yl) pyrimidin-4-ylamino] phenylamino} -3-cyano-4- (4-tert-butylaminopiperidine-1) -Il) Synthesis of quinoline hydrochloride

2- {3-Methyl-4- [2- (pyridin-3-yl) pyrimidin-4-ylamino] phenylamino} -3-cyano-4- (4-tert-butylaminopiperidine-) in DCM (3 ml) To a solution of 1-yl) quinoline (300 mg, 0.514 mmol) was added 2M HCl in diethyl ether (3.0 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture is concentrated under reduced pressure, washed with diethyl ether, and 2- {3-methyl-4- [2- (pyridin-3-yl) pyrimidin-4-ylamino] phenylamino} -3-cyano- A 230 mg (72% yield) off-white solid corresponding to 4- (4-tert-butylaminopiperidine-1-yl) quinoline hydrochloride was obtained.
Mass: ES +) C ₃₅ H ₃₈ ClN ₉ Calculated value 619.29; Measured value 584.3 [M-HCl + H], HPLC / MS Method 6.

Compounds 524-CN, 2- {3-methyl-4- [2- (pyridin-3-yl) -5-cyanopyrimidine-4-ylamino] phenylamino} -3-cyano-4- (4-tert-butyl) Preparation of Aminopiperidin-1-yl) Quinoline Hydrochloride

１，４−ジオキサン（２０ｍｌ）中の４−アミノ−５−シアノ−２−（ピリジン−３−イル）ピリミジン（５００ｍｇ、２．５３８ｍｍｏｌ）の窒素ガス下の溶液に、化合物５２２−ＣＮ−Ｉ−１（１．６９ｇ、５．０７６ｍｍｏｌ）及び炭酸セシウム（１．６５ｇ、５．０７６ｍｍｏｌ）を加えた。得られた混合液をアルゴンガスで３０分間脱気し、次にキサントホス（２９４ｍｇ、０．５０７ｍｍｏｌ）及びＰｄ_２（ｄｂａ）_３（２３２ｍｇ、０．２５３ｍｍｏｌ）を加え、反応混合液を１００℃で１２時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、減圧下で濃縮した。残留物を食塩水とＡｃＯＥｔに分配し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、褐色油状物を得た。粗化合物を、フラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＡｃＯＥｔ−石油エーテル；７０％）により精製して、４−（５−シアノ−２−（ピリジン−３−イル）ピリミジン−４−イルアミノ）−３−メチルフェニルカルバミン酸ｔｅｒｔ−ブチルに対応する０．５ｇ（収率４９％）の淡黄色固体を得た。
質量：(ES+) C₂₂H₂₂N₆O₂ 計算値 402.18; 実測値 403.1 [M+H], HPLC/MS 方法８。 Synthesis of 4- (5-cyano-2- (pyridin-3-yl) pyrimidin-4-ylamino) tert-butyl 3-methylphenylcarbamate, intermediate 524-CN-I-1

Compound 522-CN-I- in a solution of 4-amino-5-cyano-2- (pyridin-3-yl) pyrimidine (500 mg, 2.538 mmol) in 1,4-dioxane (20 ml) under nitrogen gas. 1 (1.69 g, 5.076 mmol) and cesium carbonate (1.65 g, 5.076 mmol) were added. The obtained mixture was degassed with argon gas for 30 minutes, then xantphos (294 mg, 0.507 mmol) and Pd ₂ (dba) ₃ (232 mg, 0.253 mmol) were added, and the reaction mixture was added at 100 ° C. to 12 Stir for hours. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned into saline and AcOEt, and the aqueous layer was extracted with AcOEt. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown oil. The crude compound was purified by flash chromatography (silicaline: 100-200 mesh, AcOEt-petroleum ether; 70%) to 4- (5-cyano-2- (pyridin-3-yl) pyrimidin-4-ylamino). A pale yellow solid of 0.5 g (49% yield) corresponding to tert-butyl-3-methylphenylcarbamate was obtained.
Mass: (ES +) C ₂₂ H ₂₂ N ₆ O ₂ Calculated value 402.18; Measured value 403.1 [M + H], HPLC / MS Method 8.

１，４−ジオキサン（５ｍｌ）中の化合物５２４−ＣＮ−Ｉ−１（５００ｍｇ、１．２４３ｍｍｏｌ）の溶液に、１，４−ジオキサン（５．０ｍｌ）中の４Ｍ ＨＣｌを加え、混合液を室温で４時間維持した。次に、反応混合液を減圧下で濃縮した。残留物を水（１０ｍｌ）で希釈し、次に固体重炭酸塩でクエンチし、水層をＡｃＯＥｔで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、４−［（４−アミノ−２−メチルフェニル）アミノ］−２−（ピリジン−３−イル）ピリミジン−５−カルボニトリルに対応する０．３ｇ（収率７９％）の褐色固体を得た。
質量：(ES+) C₁₇H₁₄N₆ 計算値 302.13; 実測値 303.1 [M+H], HPLC/MS 方法８。 Synthesis of 4-[(4-amino-2-methylphenyl) amino] -2- (pyridin-3-yl) pyrimidin-5-carbonitrile, intermediate 524-CN-I-2

Add 4M HCl in 1,4-dioxane (5.0 ml) to a solution of compound 524-CN-I-1 (500 mg, 1.243 mmol) in 1,4-dioxane (5 ml) and bring the mixture to room temperature. It was maintained for 4 hours. Next, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (10 ml), then quenched with solid bicarbonate and the aqueous layer was extracted with AcOEt. The combined organic layers are _{dried in Na 2} SO ₄ , filtered and concentrated under reduced pressure to 4-[(4-amino-2-methylphenyl) amino] -2- (pyridin-3-yl) pyrimidine-. A brown solid of 0.3 g (yield 79%) corresponding to 5-carbonitrile was obtained.
Mass: (ES +) C ₁₇ H ₁₄ N ₆ Calculated value 302.13; Measured value 303.1 [M + H], HPLC / MS Method 8.

１，４−ジオキサン（１０ｍｌ）中の化合物３５２−ＣＮ−Ｉ−１（０．４ｇ、１．１６９ｍｍｏｌ）の窒素ガス下の溶液に、化合物５２４−ＣＮ−Ｉ−２（０．３５ｇ、１．１６９ｍｍｏｌ）及び炭酸セシウム（０．９５３ｇ、２．８９８ｍｍｏｌ）を加えた。得られた混合液をＡｒガスで３０分間脱気し、次にキサントホス（１３５ｍｇ、０．２３３ｍｍｏｌ）及びＰｄ_２（ｄｂａ）_３（１０７ｍｇ、０．１１６９ｍｍｏｌ）を加え、反応混合液を１００℃で１時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、減圧下で濃縮した。残留物を食塩水とＡｃＯＥｔに分配し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、褐色油状物を得た。粗化合物をフラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＡｃＯＥｔ−石油エーテル；１０：９０→１５：８５）により精製して、２−｛３−メチル−４−［２−（ピリジン−３−イル）−５−シアノピリミジン−４−イルアミノ］フェニルアミノ｝−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリンに対応する１００ｍｇ（収率１４％）の白色固体を得た。
質量：(ES+) C₃₆H₃₆N₁₀ 計算値 608.31; 実測値 609 [M+H], HPLC/MS 方法４。 Free base of compound 524-CN, 2- {3-methyl-4- [2- (pyridin-3-yl) -5-cyanopyrimidine-4-ylamino] phenylamino} -3-cyano-4- (4-) Synthesis of tert-butylaminopiperidin-1-yl) quinoline

In a solution of compound 352-CN-I-1 (0.4 g, 1.169 mmol) in 1,4-dioxane (10 ml) under nitrogen gas, compound 524-CN-I-2 (0.35 g, 1.69 mmol). 169 mmol) and cesium carbonate (0.953 g, 2.898 mmol) were added. The obtained mixed solution was degassed with Ar gas for 30 minutes, then xantphos (135 mg, 0.233 mmol) and Pd ₂ (dba) ₃ (107 mg, 0.1169 mmol) were added, and the reaction mixed solution was added to the reaction mixture at 100 ° C. 1 Stir for hours. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned into saline and AcOEt, and the aqueous layer was extracted with AcOEt. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown oil. The crude compound was purified by flash chromatography (silicaline: 100-200 mesh, AcOEt-petroleum ether; 10:90 → 15:85) and 2- {3-methyl-4- [2- (pyridine-3-yl) ) -5-Cyanopyrimidin-4-ylamino] phenylamino} -3-cyano-4- (4-tert-butylaminopiperidin-1-yl) quinoline 100 mg (14% yield) of white solid rice field.
Mass: (ES +) C ₃₆ H ₃₆ N ₁₀ Calculated value 608.31; Measured value 609 [M + H], HPLC / MS Method 4.

１，４−ジオキサン（２ｍｌ）中の化合物５２４−ＣＮの遊離塩基（１００ｍｇ、０．１６４ｍｍｏｌ）の溶液に、１，４−ジオキサン（２．０ｍｌ）中の４Ｍ ＨＣｌを加え、混合液を室温で３０分攪拌した。反応混合液を減圧下で濃縮し、ジエチルエーテルで洗浄して、２−｛３−メチル−４−［２−（ピリジン−３−イル）−５−シアノピリミジン−４−イルアミノ］フェニルアミノ｝−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリン塩酸塩に対応する８５ｍｇ（収率８０％）のオフホワイトの固体を得た。
質量：(ES+) C₃₆H₃₇ClN₁₀ 計算値 644.29; 実測値 609 [M-HCl+H], HPLC/MS 方法６。 Compounds 524-CN, 2- {3-methyl-4- [2- (pyridin-3-yl) -5-cyanopyrimidine-4-ylamino] phenylamino} -3-cyano-4- (4-tert-butyl) Aminopiperidin-1-yl) Synthesis of quinoline hydrochloride

Add 4M HCl in 1,4-dioxane (2.0 ml) to a solution of the free base (100 mg, 0.164 mmol) of compound 524-CN in 1,4-dioxane (2 ml) and mix at room temperature. The mixture was stirred for 30 minutes. The reaction mixture is concentrated under reduced pressure, washed with diethyl ether, and 2- {3-methyl-4- [2- (pyridin-3-yl) -5-cyanopyrimidine-4-ylamino] phenylamino}-. An 85 mg (80% yield) off-white solid corresponding to 3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline hydrochloride was obtained.
Mass: (ES +) C ₃₆ H ₃₇ ClN ₁₀ Calculated value 644.29; Measured value 609 [M-HCl + H], HPLC / MS Method 6.

Preparation of Compounds 532-CN, 2- [4- (4-Methylpyrimidine-2-ylamino) phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline hydrochloride

１，４−ジオキサン（４ｍｌ）中の（４−メチルピリミジン−２−イルアミノ）−４−フェニルアミン（０．２ｇ、０．５８５ｍｍｏｌ）の窒素ガス下の溶液に、化合物３５２−ＣＮ−Ｉ−１（０．１７５ｇ、０．８７７ｍｍｏｌ）及びｔ−ＢｕＯＮａ（０．１７０ｇ、１．７５４ｍｍｏｌ）を加えた。得られた混合液をＡｒガスで３０分間脱気し、次にキサントホス（３３．８ｍｇ、０．０５８４ｍｍｏｌ）及びＰｄ（ＯＡＣ）_２（１３ｍｇ、０．０５８４ｍｍｏｌ）を加え、反応混合液を１００℃で３時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、減圧下で濃縮した。残留物を食塩水とＡｃＯＥｔに分配し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、褐色油状物を得た。粗化合物をフラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＡｃＯＥｔ−石油エーテル；１０：９０→１５：８５）により精製して、２−［４−（４−メチルピリミジン−２−イルアミノ）フェニルアミノ］−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリンに対応する５０ｍｇ（収率１６．８％）の白色固体を得た。
質量：(ES+) C₃₀H₃₄N₈ 計算値 506.29 ; 実測値 507.22 [M+H], HPLC/MS 方法４。 Synthesis of 2- [4- (4-methylpyrimidine-2-ylamino) phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline, a free base of compound 532-CN

Compound 352-CN-I-1 in a solution of (4-methylpyrimidine-2-ylamino) -4-phenylamine (0.2 g, 0.585 mmol) in 1,4-dioxane (4 ml) under nitrogen gas. (0.175 g, 0.877 mmol) and t-BuONa (0.170 g, 1.754 mmol) were added. The obtained mixed solution was degassed with Ar gas for 30 minutes, then xantphos (33.8 _{mg, 0.0584 mmol) and Pd (OAC) 2} (13 mg, 0.0584 mmol) were added, and the reaction mixed solution was prepared at 100 ° C. The mixture was stirred for 3 hours. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned into saline and AcOEt, and the aqueous layer was extracted with AcOEt. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown oil. The crude compound was purified by flash chromatography (silicaline: 100-200 mesh, AcOEt-petroleum ether; 10:90 → 15:85) to 2- [4- (4-methylpyrimidine-2-ylamino) phenylamino]. A 50 mg (16.8% yield) white solid corresponding to -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline was obtained.
Mass: (ES +) C ₃₀ H ₃₄ N ₈ Calculated value 506.29; Measured value 507.22 [M + H], HPLC / MS Method 4.

ＤＣＭ（１ｍｌ）中の化合物５３２−ＣＮの遊離塩基（５０ｍｇ、０．０９８８ｍｍｏｌ）の溶液に、ジエチルエーテル（１．０ｍｌ）中の２Ｍ ＨＣｌを加え、得られた混合液を室温で３０分間撹拌した。反応混合液を減圧下で濃縮し、ジエチルエーテルで洗浄して、２−［４−（４−メチルピリミジン−２−イルアミノ）フェニルアミノ］−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリン塩酸塩に対応する４０ｍｇ（収率７５％）のオフホワイト色の固体を得た。
質量：(ES+) C₃₀H₃₅ClN₈ 計算値 542.27; 実測値 507 [M-HCl+H], HPLC/MS 方法４。 Synthesis of Compounds 532-CN, 2- [4- (4-Methylpyrimidine-2-ylamino) phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline hydrochloride

2M HCl in diethyl ether (1.0 ml) was added to a solution of the free base (50 mg, 0.0988 mmol) of compound 532-CN in DCM (1 ml) and the resulting mixture was stirred at room temperature for 30 minutes. .. The reaction mixture is concentrated under reduced pressure, washed with diethyl ether, and 2- [4- (4-methylpyrimidine-2-ylamino) phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine). A 40 mg (75% yield) off-white solid corresponding to -1-yl) quinoline hydrochloride was obtained.
Mass: (ES +) C ₃₀ H ₃₅ ClN ₈ Calculated value 542.27; Measured value 507 [M-HCl + H], HPLC / MS Method 4.

Compounds 534-CN, 2- [3-Methyl-4- (4-trifluoromethylpyrimidine-2-ylamino) phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline Preparation of hydrochloride

濃ＨＣｌ水溶液を、１０％エタノール水溶液中の２−アミノ−５−ニトロトルエン（２ｇ、１３．１５ｍｍｏｌ）及び２−クロロ−４−トリフルオロメチルピリミジン（２．３９ｇ、１３．１５ｍｍｏｌ）の撹拌溶液に加えた。反応混合液を８０℃で１６時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、減圧下で濃縮した。残留物を食塩水とＥｔＯＡｃで分配し、水層をＥｔＯＡｃで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して黄色固体を得た。粗化合物を、フラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＡｃＯＥｔ−石油エーテル；２０：８０）により精製して、Ｎ−（２−メチル−４−ニトロフェニル）−４−（トリフルオロメチル）ピリミジン−２−アミンに対応する８００ｍｇ（収率２５％）お黄色固体を得た。
質量：(ES+) C₁₂H₉F₃N₄O₂計算値 298.07; 実測値 299.0 [M+H], HPLC/MS 方法６。 Synthesis of N- (2-Methyl-4-nitrophenyl) -4- (trifluoromethyl) pyrimidin-2-amine intermediate, 534-CN-I-1

Add concentrated HCl aqueous solution to a stirred solution of 2-amino-5-nitrotoluene (2 g, 13.15 mmol) and 2-chloro-4-trifluoromethylpyrimidine (2.39 g, 13.15 mmol) in a 10% ethanol aqueous solution. rice field. The reaction mixture was stirred at 80 ° C. for 16 hours. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned between saline and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a yellow solid. The crude compound was purified by flash chromatography (silica gel: 100-200 mesh, AcOEt-petroleum ether; 20:80) and N- (2-methyl-4-nitrophenyl) -4- (trifluoromethyl) pyrimidine. An 800 mg (25% yield) yellow solid corresponding to -2-amine was obtained.
Mass: (ES +) C ₁₂ H ₉ F ₃ N ₄ O ₂ Calculated value 298.07; Measured value 299.0 [M + H], HPLC / MS Method 6.

室温でエタノール中の化合物−５３４−ＣＮ−Ｉ−１（０．８ｇ、２．６８４ｍｍｏｌ）の撹拌溶液に１０％Ｐｄ−Ｃを加え、反応混合液を水素下（５０ｐｓｉ）室温で５時間攪拌した。次に、反応混合液を濾過し、減圧下で濃縮して、褐色油状物を得た。粗化合物をエーテルで洗浄して、２−メチル−Ｎ^１−（４−（トリフルオロメチル）ピリミジン−２−イル）ベンゼン−１，４−ジアミンに対応する５００ｍｇ（収率６９．３％）の黄色固体を得た。
質量：(ES+) C₁₂H₁₁F₃N₄ 計算値 268.09.26; 実測値 269.1 [M+H], HPLC/MS 方法６。 Synthesis of 2-methyl-N ^1- (4- (trifluoromethyl) pyrimidin-2-yl) benzene-1,4-diamine, intermediate 534-CN-I-2

10% Pd-C was added to a stirred solution of compound-534-CN-I-1 (0.8 g, 2.684 mmol) in ethanol at room temperature, and the reaction mixture was stirred under hydrogen (50 psi) at room temperature for 5 hours. .. The reaction mixture was then filtered and concentrated under reduced pressure to give a brown oil. The crude compound was washed with ether, 2-methyl ^-N 1 - (4 (trifluoromethyl) pyrimidin-2-yl) 500 mg corresponding to benzene-1,4-diamine (69.3% yield) A yellow solid was obtained.
Mass: (ES +) C ₁₂ H ₁₁ F ₃ N ₄ Calculated value 268.09.26; Measured value 269.1 [M + H], HPLC / MS Method 6.

ＴＨＦ（１５ｍｌ）中の化合物３５２−ＣＮ−Ｉ−１（０．３ｇ、０．８７５ｍｍｏｌ）の窒素ガス下の溶液に、化合物−５３４−ＣＮ−Ｉ−２（０．２３５ｇ、０．８７７５ｍｍｏｌ）及びｔ−ＢｕＯＮａ（０．２５５ｇ、２．６２５ｍｍｏｌ）を加えた。得られた混合液をＡｒガスで３０分間脱気し、次にキサントホス（５０．０ｍｇ、０．０８７ｍｍｏｌ）及びＰｄ（ＯＡｃ）_２（１０．０ｍｇ、０．０４４ｍｍｏｌ）を加え、反応混合液を８０℃で３時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、減圧下で濃縮した。残留物を食塩水とＡｃＯＥｔに分配し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、褐色油状物を得た。粗化合物をフラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、０〜１０％ＭｅＯＨ：ＤＣＭ）により精製して、２−［３−メチル−４−（４−トリフルオロメチルピリミジン−２−イルアミノ）フェニルアミノ］−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリンに対応する５０ｍｇ（収率１０％）の白色固体を得た。
質量：(ES+) C₃₁H₃₃F₃N₈ 計算値 574.28.26; 実測値 575.2M+H], HPLC/MS 方法６。 Free base of compound 534-CN, 2- [3-methyl-4- (4-trifluoromethylpyrimidine-2-ylamino) phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-) Il) Quinoline synthesis

In a solution of compound 352-CN-I-1 (0.3 g, 0.875 mmol) in THF (15 ml) under nitrogen gas, compound-534-CN-I-2 (0.235 g, 0.8775 mmol) and t-BuONa (0.255 g, 2.625 mmol) was added. The obtained mixture is degassed with Ar gas for 30 minutes, then xantphos (50.0 mg, 0.087 mmol) and Pd (OAc) ₂ (10.0 mg, 0.044 mmol) are added, and the reaction mixture is 80. The mixture was stirred at ° C. for 3 hours. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned into saline and AcOEt, and the aqueous layer was extracted with AcOEt. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown oil. The crude compound is purified by flash chromatography (silicaline: 100-200 mesh, 0-10% MeOH: DCM) and 2- [3-methyl-4- (4-trifluoromethylpyrimidine-2-ylamino) phenylamino. ] -3-Cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline corresponding to 50 mg (10% yield) of white solid was obtained.
Mass: (ES +) C ₃₁ H ₃₃ F ₃ N ₈ Calculated value 574.28.26; Measured value 575.2 M + H], HPLC / MS Method 6.

ＤＣＭ（１ｍｌ）中の化合物５３４−ＣＮの遊離塩基（５０ｍｇ、５７４．２８ｍｍｏｌ）の溶液に、ジエチルエーテル（１．０ｍｌ）中の２Ｍ ＨＣｌを加え、得られた混合液を室温で３０分間撹拌した。反応混合液を減圧下で濃縮し、ジエチルエーテルで洗浄して、２−［３−メチル−４−（４−トリフルオロメチルピリミジン−２−イルアミノ）フェニルアミノ］−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリン塩酸塩の４０ｍｇ（収率７１％）のオフホワイトの固体を得た。
質量：(ES+) C₃₁H₃₄F₃ClN₈ 計算値 610.25; 実測値 575.2 (M-HCl+H], HPLC 方法４。 Compounds 534-CN, 2- [3-Methyl-4- (4-trifluoromethylpyrimidine-2-ylamino) phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline Synthesis of hydrochloride

2M HCl in diethyl ether (1.0 ml) was added to a solution of the free base (50 mg, 574.28 mmol) of compound 534-CN in DCM (1 ml) and the resulting mixture was stirred at room temperature for 30 minutes. .. The reaction mixture is concentrated under reduced pressure, washed with diethyl ether, and 2- [3-methyl-4- (4-trifluoromethylpyrimidine-2-ylamino) phenylamino] -3-cyano-4- (4). An off-white solid of 40 mg (71% yield) of -tert-butylaminopiperidine-1-yl) quinoline hydrochloride was obtained.
Mass: (ES +) C ₃₁ H ₃₄ F ₃ ClN ₈ Calculated value 610.25; Measured value 575.2 (M-HCl + H], HPLC method 4.

Compound of Example 538-CN, 2- [3- (4-trifluoromethylpyrimidine-2-ylamino) -4-methyl-phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1) -Il) -Preparation of quinoline hydrochloride

１，４−ジオキサン（２０ｍｌ）中の２−クロロ−４−（トリフルオロメチル）ピリミジン（１．０ｇ、５．４７ｍｍｏｌ）の窒素ガス下の溶液に、２−メチル−５−ニトロアニリン（１．０ｇ、６．５ｍｍｏｌ）及び炭酸セシウム（４．６４ｇ、１４．２５ｍｍｏｌ）を加えた。得られた混合液をアルゴンガスで３０分間脱気し、次にキサントホス（３３０ｍｇ、０．５７ｍｍｏｌ）及びＰｄ_２（ｄｂａ）_３（５２０ｍｇ、０．５７ｍｍｏｌ）を加え、反応混合液を１００℃で６時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、減圧下で濃縮した。残留物を食塩水とＡｃＯＥｔに分配し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、褐色油状物を得た。粗化合物を、フラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＡｃＯＥｔ−石油エーテル；３０％）により精製して、Ｎ−（２−メチル−５−ニトロフェニル）−４−（トリフルオロメチル）ピリミジン−２−アミンに対応する０．５ｇ（収率３１％）の淡黄色固体を得た。
質量：ES+) C₁₂H₉F₃N₄O₂ 計算値 298; 実測値 299 [M+H], HPLC/MS 方法４。 Synthesis of N- (2-methyl-5-nitrophenyl) -4- (trifluoromethyl) pyrimidin-2-amine, intermediate 538-CN-I-1

2-Methyl-5-nitroaniline (1.) in a solution of 2-chloro-4- (trifluoromethyl) pyrimidine (1.0 g, 5.47 mmol) in 1,4-dioxane (20 ml) under nitrogen gas. 0 g, 6.5 mmol) and cesium carbonate (4.64 g, 14.25 mmol) were added. The obtained mixture is degassed with argon gas for 30 minutes, then xantphos (330 mg, _{0.57 mmol) and Pd 2} (dba) ₃ (520 mg, 0.57 mmol) are added, and the reaction mixture is mixed at 100 ° C. 6 Stir for hours. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned into saline and AcOEt, and the aqueous layer was extracted with AcOEt. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown oil. The crude compound was purified by flash chromatography (silica gel: 100-200 mesh, AcOEt-petroleum ether; 30%) and N- (2-methyl-5-nitrophenyl) -4- (trifluoromethyl) pyrimidine-. A pale yellow solid of 0.5 g (31% yield) corresponding to 2-amine was obtained.
Mass: ES +) C ₁₂ H ₉ F ₃ N ₄ O ₂ Calculated value 298; Measured value 299 [M + H], HPLC / MS Method 4.

ＥｔＯＨ（１５ｍｌ）中のＮ−（２−メチル−５−ニトロフェニル）−４−（トリフルオロメチル）ピリミジン−２−アミン（０．５ｇ、１．６７ｍｍｏｌ）の溶液に、１０％Ｐｄ／Ｃ（５０ｍｇ）を加えた。得られた混合液を水素下（１バール）で６時間撹拌した。触媒を濾別し、ＥｔＯＨで洗浄し、溶媒を減圧下で濃縮して、６−メチル−Ｎ^１−（４−（トリフルオロメチル）ピリミジン−２−イル）ベンゼン−１，３−ジアミンに対応する０．３５ｇ（収率７７．７％）の淡褐色固体を得た。
質量：ES+) C₁₂H₁₁F₃N₄ 計算値 268; 実測値 269 [M+H], HPLC/MS 方法２。 Synthesis of 6-methyl-N ^1- [4- (trifluoromethyl) pyrimidin-2-yl] benzene-1,3-diamine, intermediate 538-CN-I-2

A solution of N- (2-methyl-5-nitrophenyl) -4- (trifluoromethyl) pyrimidin-2-amine (0.5 g, 1.67 mmol) in EtOH (15 ml) at 10% Pd / C ( 50 mg) was added. The resulting mixture was stirred under hydrogen (1 bar) for 6 hours. The catalyst was filtered off, washed with EtOH, the solvent was concentrated under reduced pressure, 6-methyl ^-N 1 - corresponds to (4- (trifluoromethyl) pyrimidin-2-yl) benzene-1,3-diamine A light brown solid of 0.35 g (yield 77.7%) was obtained.
Mass: ES +) C ₁₂ H ₁₁ F ₃ N ₄ Calculated value 268; Measured value 269 [M + H], HPLC / MS Method 2.

１，４−ジオキサン（２５ｍｌ）中の２−［３−（４−トリフルオロメチル−２−ピリミジンアミノ）−４−メチル−フェニルアミノ］−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）−キノリン、３５２−ＣＮ−Ｉ−１（０．４５ｇ、１．３ｍｍｏｌ）の窒素ガス下の溶液に、６−メチル−Ｎ^１−（４−（トリフルオロメチル）ピリミジン−２−イル）ベンゼン−１，３−ジアミン、５３８−ＣＮ−Ｉ−２（０．３５ｇ、１．３ｍｍｏｌ）及びｔ−ＢｕＯＮａ（３１２ｍｇ、３．２５ｍｍｏｌ）を加えた。得られた混合液をアルゴンガスで３０分間脱気し、次にキサントホス（６２ｍｇ、０．１３ｍｍｏｌ）及びＰｄ（ＯＡｃ）_２（２９ｍｇ、０．１３ｍｍｏｌ）を加え、反応混合液を１００℃で１６時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、減圧下で濃縮した。残留物を食塩水とＡｃＯＥｔに分配し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、褐色油状物を得た。粗化合物をフラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、４％ＭｅＯＨ−ＣＨ_２Ｃｌ_２）により２回精製して、２−［３−（４−トリフルオロメチル−２−ピリミジンアミノ）−４−メチル−フェニルアミノ］−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）−キノリンに対応する３０ｍｇ（収率４％）の淡褐色の固体を得た。
質量：(ES+) C₃₁H₃₃F₃N₈ 計算値 574; 実測値 575 [M+H], HPLC 方法２。 Free base of compound 538-CN, 2- [3- (4-trifluoromethylpyrimidine-2-ylamino) -4-methyl-phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1) -Il) -Quinoline synthesis

2- [3- (4-Trifluoromethyl-2-pyrimidineamino) -4-methyl-phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine) in 1,4-dioxane (25 ml) -1-Il) -quinolin, 352-CN-I-1 (0.45 g, 1.3 mmol) in a solution under nitrogen gas, 6-methyl-N ^1- (4- (trifluoromethyl) piperidine-2) -Il) Benzene-1,3-diamine, 538-CN-I-2 (0.35 g, 1.3 mmol) and t-BuONa (312 mg, 3.25 mmol) were added. The obtained mixture is degassed with argon gas for 30 minutes, then xantphos (62 mg, 0.13 mmol) and Pd (OAc) ₂ (29 mg, 0.13 mmol) are added, and the reaction mixture is heated at 100 ° C. for 16 hours. Stirred. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned into saline and AcOEt, and the aqueous layer was extracted with AcOEt. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown oil. The crude compound was purified twice by flash chromatography (silicaline: 100-200 mesh, 4% MeOH-CH ₂ Cl ₂ ) and 2- [3- (4-trifluoromethyl-2-pyrimidineamino) -4-. A light brown solid of 30 mg (4% yield) corresponding to methyl-phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) -quinoline was obtained.
Mass: (ES +) C ₃₁ H ₃₃ F ₃ N ₈ Calculated 574; Measured 575 [M + H], HPLC Method 2.

１，４−ジオキサン（５ｍｌ）中の２−［３−（４−トリフルオロメチル−２−ピリミジンアミノ）−４−メチル−フェニルアミノ］−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）−キノリン（０．０３ｇ、０．０５ｍｍｏｌ）の溶液に、０℃で１，４−ジオキサン（５．０ｍｌ）中の４Ｍ ＨＣｌを加え、混合液を室温で６時間撹拌した。次に、反応混合液を減圧下で濃縮し、ジエチルエーテルで洗浄して、２−［３−（４−トリフルオロメチル−２−ピリミジンアミノ）−４−メチル−フェニルアミノ］−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）−キノリン塩酸塩に対応する２５ｍｇ（収率７８％）のオフホワイトの固体を得た。
質量：(ES+) C₃₁H₃₄ClF3N₈ 計算値 574(M-HCl); 実測値 575 [(M-HCl) +H]⁺, HPLC/MS 方法５。 Compounds 538-CN, 2- [3- (4-trifluoromethylpyrimidine-2-ylamino) -4-methyl-phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) -Synthesis of quinoline hydrochloride

2- [3- (4-Trifluoromethyl-2-pyrimidineamino) -4-methyl-phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine) in 1,4-dioxane (5 ml) To a solution of -1-yl) -quinoline (0.03 g, 0.05 mmol) was added 4M HCl in 1,4-dioxane (5.0 ml) at 0 ° C. and the mixture was stirred at room temperature for 6 hours. Next, the reaction mixture is concentrated under reduced pressure, washed with diethyl ether, and 2- [3- (4-trifluoromethyl-2-pyrimidineamino) -4-methyl-phenylamino] -3-cyano- A 25 mg (78% yield) off-white solid corresponding to 4- (4-tert-butylaminopiperidine-1-yl) -quinoline hydrochloride was obtained.
Mass: (ES +) C ₃₁ H ₃₄ ClF3N ₈ Calculated value 574 (M-HCl); Measured value 575 [(M-HCl) + H] ⁺ , HPLC / MS Method 5.

Preparation of Compounds 540-CN, 2- [3- (4-trifluoromethylpyrimidine-2-ylamino) phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline hydrochloride

１，４−ジオキサン（４ｍｌ）中の化合物３５２−ＣＮ−Ｉ−１（０．２ｇ、０．５８５ｍｍｏｌ）の窒素ガス下の溶液に、化合物５４０−Ｍｅ−Ｉ−１（０．２２２ｇ、０．８７７ｍｍｏｌ）及びｔ−ＢｕＯＮａ（０．１７０ｇ、１．７５４ｍｍｏｌ）を加えた。得られた混合液をＡｒガスで３０分間脱気し、次にキサントホス（３３．８ｍｇ、０．０５８４ｍｍｏｌ）及びＰｄ（ＯＡＣ）_２（１３ｍｇ、０．０５８４ｍｍｏｌ）を加え、反応混合液を１００℃で３時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、減圧下で濃縮した。残留物を食塩水とＡｃＯＥｔに分配し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、褐色油状物を得た。粗化合物をフラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＡｃＯＥｔ−石油エーテル；１０：９０→１５：８５）により精製して、２−［３−（４−トリフルオロメチルピリミジン−２−イルアミノ）フェニルアミノ］−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリンに対応する７０ｍｇ（収率２１％）の白色固体を得た。
質量：(ES+) C₃₀H₃₁F₃N₈ 計算値 560.26; 実測値 561.22 [M+H], HPLC/MS 方法４。 2- [3- (4-Trifluoromethylpyrimidine-2-ylamino) phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline, of the compound of Example 540-CN. Free base synthesis

In a solution of compound 352-CN-I-1 (0.2 g, 0.585 mmol) in 1,4-dioxane (4 ml) under nitrogen gas, compound 540-Me-I-1 (0.222 g, 0.22 g, 0. 877 mmol) and t-BuONa (0.170 g, 1.754 mmol) were added. The obtained mixed solution was degassed with Ar gas for 30 minutes, then xantphos (33.8 _{mg, 0.0584 mmol) and Pd (OAC) 2} (13 mg, 0.0584 mmol) were added, and the reaction mixed solution was prepared at 100 ° C. The mixture was stirred for 3 hours. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned into saline and AcOEt, and the aqueous layer was extracted with AcOEt. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown oil. The crude compound was purified by flash chromatography (silicaline: 100-200 mesh, AcOEt-petroleum ether; 10:90 → 15:85) to 2- [3- (4-trifluoromethylpyrimidine-2-ylamino) phenyl. Amino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline corresponding to 70 mg (21% yield) of white solid was obtained.
Mass: (ES +) C ₃₀ H ₃₁ F ₃ N ₈ Calculated value 560.26; Measured value 561.22 [M + H], HPLC / MS Method 4.

ＤＣＭ（２ｍｌ）中の化合物５４０−ＣＮの遊離塩基（７０ｍｇ、０．１２５ｍｍｏｌ）の溶液に、ジエチルエーテル（２．０ｍｌ）中の２Ｍ ＨＣｌを加え、混合液を室温で３０分間撹拌した。次に、反応混合液を減圧下で濃縮し、ジエチルエーテルで洗浄して、２−［３−（４−トリフルオロメチルピリミジン−２−イルアミノ）フェニルアミノ］−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリン塩酸塩に対応する６７ｍｇ（収率９０％）のオフホワイトの固体を得た。
質量：ES+) C₃₀H₃₂ClF₃N₈ 計算値 596; 実測値 559 [M-HCl-H]⁺, HPLC/MS 方法４。 Synthesis of Compounds 540-CN, 2- [3- (4-trifluoromethylpyrimidine-2-ylamino) phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline hydrochloride

2M HCl in diethyl ether (2.0 ml) was added to a solution of the free base (70 mg, 0.125 mmol) of compound 540-CN in DCM (2 ml) and the mixture was stirred at room temperature for 30 minutes. Next, the reaction mixture is concentrated under reduced pressure, washed with diethyl ether, and 2- [3- (4-trifluoromethylpyrimidine-2-ylamino) phenylamino] -3-cyano-4- (4-). A 67 mg (90% yield) off-white solid corresponding to tert-butylaminopiperidin-1-yl) quinoline hydrochloride was obtained.
Mass: ES +) C ₃₀ H ₃₂ ClF ₃ N ₈ Calculated value 596; Measured value 559 [M-HCl-H] ⁺ , HPLC / MS Method 4.

Compounds 3131-CN, 2- [4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) -3-methylphenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1) -Il) Preparation of quinoline hydrochloride

１，４−ジオキサン（１０ｍｌ）中の４−（ピリジン−３−イル）−２−クロロピリミジン（２００ｍｇ、１．０４７ｍｍｏｌ）の窒素ガス下の溶液に、２−メチル−４−ニトロアニリン（１５９ｍｇ、１．０４７ｍｍｏｌ）及び炭酸セシウム（６８２ｍｇ、２．０９４ｍｍｏｌ）を加えた。得られた混合液をアルゴンガスで３０分間脱気し、次にキサントホス（６１ｍｇ、０．１０４７ｍｍｏｌ）及びＰｄ_２（ｄｂａ）_３（９６ｍｇ、０．１０４７ｍｍｏｌ）を加え、反応混合液を１００℃で４時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、減圧下で濃縮した。残留物を食塩水とＡｃＯＥｔに分配し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、褐色油状物を得た。粗化合物を、フラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＡｃＯＥｔ−石油エーテル；７０％）により精製して、Ｎ−（２−メチル−４−ニトロフェニル）−４−（ピリジン−３−イル）ピリミジン−２−アミンに対応する０．２ｇ（収率６２％）の淡黄色固体を得た。
質量：ES+) C₁₆H₁₃N₅O₂ 計算値 307.11; 実測値 308.1 [M+H], 方法８。 Synthesis of N- (2-methyl-4-nitrophenyl) -4- (pyridin-3-yl) pyrimidin-2-amine, intermediate 3131-CN-I-1

2-Methyl-4-nitroaniline (159 mg, 159 mg,) in a solution of 4- (pyridin-3-yl) -2-chloropyrimidine (200 mg, 1.047 mmol) under nitrogen gas in 1,4-dioxane (10 ml). 1.047 mmol) and cesium carbonate (682 mg, 2.094 mmol) were added. The obtained mixture was degassed with argon gas for 30 minutes, then xantphos (61 mg, 0.1047 mmol) and Pd ₂ (dba) ₃ (96 mg, 0.1047 mmol) were added, and the reaction mixture was mixed at 100 ° C. 4 Stir for hours. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned into saline and AcOEt, and the aqueous layer was extracted with AcOEt. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown oil. The crude compound is purified by flash chromatography (silica gel: 100-200 mesh, AcOEt-petroleum ether; 70%) to N- (2-methyl-4-nitrophenyl) -4- (pyridin-3-yl). A pale yellow solid of 0.2 g (yield 62%) corresponding to pyrimidine-2-amine was obtained.
Mass: ES +) C ₁₆ H ₁₃ N ₅ O ₂ Calculated value 307.11; Measured value 308.1 [M + H], Method 8.

ＥｔＯＨ（２０ｍｌ）中の化合物３１３１−ＣＮ−Ｉ−２（０．２ｇ、０．６５１ｍｍｏｌ）の溶液に１０％Ｐｄ／Ｃ（２０ｍｇ）を加えた。得られた混合液を水素下（１バール）で１６時間撹拌した。触媒を濾別し、ＥｔＯＨで洗浄し、溶媒を減圧下で濃縮して、２−メチル−Ｎ^１−（４−（ピリジン−３−イル）ピリミジン−２−イル）ベンゼン−１，３−ジアミンに対応する０．１５ｇ（収率８３％）の淡褐色固体を得た。
質量：ES+) C₁₆H₁₅N₅ 計算値 277.13; 実測値 278 [M+H], HPLC/MS 方法８。 Synthesis of 2-methyl-N ^1- (4- (pyridin-3-yl) pyrimidin-2-yl) benzene-1,4-diamine, intermediate 3131-CN-I-2

10% Pd / C (20 mg) was added to a solution of compound 3131-CN-I-2 (0.2 g, 0.651 mmol) in EtOH (20 ml). The resulting mixture was stirred under hydrogen (1 bar) for 16 hours. The catalyst is filtered off, washed with EtOH, the solvent is concentrated under reduced pressure and 2-methyl-N- ^1- (4- (pyridin-3-yl) pyrimidin-2-yl) benzene-1,3-diamine. A light brown solid of 0.15 g (yield 83%) corresponding to the above was obtained.
Mass: ES +) C ₁₆ H ₁₅ N ₅ Calculated value 277.13; Measured value 278 [M + H], HPLC / MS Method 8.

１，４−ジオキサン（４ｍｌ）中の３５２−ＣＮ−Ｉ−１（０．２ｇ、０．５８５ｍｍｏｌ）の窒素ガス下の溶液に、３１３１−ＣＮ−Ｉ−２（０．１６ｇ、０．５８５ｍｍｏｌ）及びｔ−ＢｕＯＮａ（０．１７０ｇ、１．７５４ｍｍｏｌ）を加えた。得られた混合液をＡｒガスで３０分間脱気し、次にキサントホス（３３．８ｍｇ、０．０５８４ｍｍｏｌ）及びＰｄ_２（ｄｂａ）_３（５３．５ｍｇ、０．０５８４ｍｍｏｌ）を加え、反応混合液を１００℃で３時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、減圧下で濃縮した。残留物を食塩水とＡｃＯＥｔに分配し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、褐色油状物を得た。粗化合物をフラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＡｃＯＥｔ−石油エーテル；１０：９０→１５：８５）により精製して、２−｛４−［４−（ピリジン−３−イル）ピリミジン−２−イルアミノ］−３−メチルフェニルアミノ｝−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリンに対応する４０ｍｇ（収率１２％）の白色固体を得た。
質量：ES+) C₃₅H₃₇N₉ 計算値 583.32; 実測値 584.22 [M+H], HPLC/MS 方法８。 Free base of compound 3131-CN, 2- {4- [4- (pyridin-3-yl) pyrimidin-2-ylamino] -3-methylphenylamino} -3-cyano-4- (4-tert-butylamino) Piperidine-1-yl) Synthesis of quinoline

3131-CN-I-2 (0.16 g, 0.585 mmol) in a solution of 352-CN-I-1 (0.2 g, 0.585 mmol) in 1,4-dioxane (4 ml) under nitrogen gas. And t-BuONa (0.170 g, 1.754 mmol) were added. The obtained mixed solution was degassed with Ar gas for 30 minutes, then xantphos (33.8 mg, 0.0584 mmol) and Pd ₂ (dba) ₃ (53.5 mg, 0.0584 mmol) were added, and the reaction mixed solution was added. The mixture was stirred at 100 ° C. for 3 hours. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned into saline and AcOEt, and the aqueous layer was extracted with AcOEt. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown oil. The crude compound was purified by flash chromatography (silicaline: 100-200 mesh, AcOEt-petroleum ether; 10:90 → 15:85) and 2- {4- [4- (pyridin-3-yl) pyrimidin-2. -Ilamino] -3-Methylphenylamino} -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) A white solid of 40 mg (yield 12%) corresponding to quinoline was obtained.
Mass: ES +) C ₃₅ H ₃₇ N ₉ Calculated value 583.32; Measured value 584.22 [M + H], HPLC / MS Method 8.

ジオキサン（１ｍｌ）中の２−｛４−［４−（ピリジン−３−イル）ピリミジン−２−イルアミノ］−３−メチルフェニルアミノ｝−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリン（４０ｍｇ、０．１０３ｍｍｏｌ）の溶液に、１，４−ジオキサン（１．０ｍｌ）中の４Ｍ ＨＣｌを加え、混合液を室温で３０分間撹拌した。反応混合液を減圧下で濃縮し、ジエチルエーテルで洗浄して、２−［４−（４−（ピリジン−３−イル）ピリミジン−２−イルアミノ）−３−メチルフェニルアミノ］−３−シアノ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリン塩酸塩に対応する３０ｍｇ（収率７１％）の白色固体を得た。
質量：(ES+) C₃₅H₃₈ClN₉ 計算値 619.29 ; 実測値 584 [M-HCl+H], HPLC/MS 方法６。 Compounds 3131-CN, 2- [4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) -3-methylphenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1) -Il) Synthesis of quinoline hydrochloride

2- {4- [4- (Pyridine-3-yl) pyrimidin-2-ylamino] -3-methylphenylamino} -3-cyano-4- (4-tert-butylaminopiperidin-) in dioxane (1 ml) To a solution of 1-yl) quinoline (40 mg, 0.103 mmol) was added 4M HCl in 1,4-dioxane (1.0 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture is concentrated under reduced pressure, washed with diethyl ether, and 2- [4- (4- (pyridin-3-yl) pyrimidin-2-ylamino) -3-methylphenylamino] -3-cyano-. A 30 mg (71% yield) white solid corresponding to 4- (4-tert-butylaminopiperidine-1-yl) quinoline hydrochloride was obtained.
Mass: (ES +) C ₃₅ H ₃₈ ClN ₉ Calculated value 619.29; Measured value 584 [M-HCl + H], HPLC / MS Method 6.

Compound of Example 540-F, 2- [3- (4-trifluoromethylpyrimidine-2-ylamino) phenylamino] -3-fluoro-4- (4-tert-butylaminopiperidine-1-yl) quinoline hydrochloride Preparation of salt

１，４−ジオキサン（４ｍｌ）中の２，４−ジクロロ−３−フルオロキノリン（０．１ｇ、０．４６５ｍｍｏｌ）の窒素ガス下の溶液に、化合物中間体５４０−Ｍｅ−Ｉ−１（１４１．７ｍｇ、０．５５８ｍｍｏｌ）及びＫ_２ＣＯ_３（０．１５８ｇ、１．１４５ｍｍｏｌ）を加えた。得られた混合液をＡｒガスで５分間脱気し、次にキサントホス（２６．９ｍｇ、０．０４６ｍｍｏｌ）及びＰｄ_２（ｄｂａ）_３（２１．３ｍｇ、０．０２３ｍｍｏｌ）を加え、反応混合液を１００℃で２時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、減圧下で濃縮した。残留物を食塩水とＡｃＯＥｔに分配し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、褐色油状物を得た。粗化合物をフラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＡｃＯＥｔ−石油エーテル；１０：９０→１５：８５）により精製して、２−［３−（４−トリフルオロメチルピリミジン−２−イルアミノ）フェニルアミノ］−３−フルオロ−４−クロロキノリンに対応する１１０ｍｇ（収率５５％）の白色固体を得た。
質量：(ES+) C₂₀H₁₂ClF₄N₅ 計算値 433.07; 実測値 434.1 [M+H], HPLC/MS 方法４。 Synthesis of 2- [3- (4-trifluoromethylpyrimidine-2-ylamino) phenylamino] -3-fluoro-4-chloroquinoline, intermediate 540-FI-1

In a solution of 2,4-dichloro-3-fluoroquinoline (0.1 g, 0.465 mmol) in 1,4-dioxane (4 ml) under nitrogen gas, compound intermediate 540-Me-I-1 (141. 7 mg, 0.558 mmol) and _{K 2 CO 3 (0.158g, 1.145mmol} ) was added. The obtained mixed solution was degassed with Ar gas for 5 minutes, then xantphos (26.9 mg, 0.046 mmol) and Pd ₂ (dba) ₃ (21.3 mg, 0.023 mmol) were added, and the reaction mixed solution was added. The mixture was stirred at 100 ° C. for 2 hours. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned into saline and AcOEt, and the aqueous layer was extracted with AcOEt. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown oil. The crude compound was purified by flash chromatography (silica gel: 100-200 mesh, AcOEt-petroleum ether; 10:90 → 15:85) to 2- [3- (4-trifluoromethylpyrimidine-2-ylamino) phenyl. A 110 mg (55% yield) white solid corresponding to amino] -3-fluoro-4-chloroquinoline was obtained.
Mass: (ES +) C ₂₀ H ₁₂ ClF ₄ N ₅ Calculated value 433.07; Measured value 434.1 [M + H], HPLC / MS Method 4.

ＮＭＰ（２ｍｌ）中の化合物５４０−ＦＩ−１（１００ｍｇ、０．２３０ｍｍｏｌ）の溶液に、４−（ｔｅｒｔ−ブチルアミノ）ピペリジン（１０８ｍｇ、０．６９２ｍｍｏｌ）、続いてＤｉＰＥＡ（０．０６ｍｌ、０．３４５ｍｍｏｌ）を加え、得られた混合液を２２０℃でマイクロ波中で５時間撹拌した。次に、反応混合液を室温に冷却し、氷水及びＡｃＯＥｔで希釈し、水層をＡｃＯＥｔで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮してオフホワイトの固体を得た。得られた固体を、フラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＭｅＯＨ−ＤＣＭ；０５：９５→１０：９０）により精製して、２−［３−（４−トリフルオロメチルピリミジン−２−イルアミノ）フェニルアミノ］−３−フルオロ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリンに対応する０．４ｇ（収率３１％）のオフホワイトの固体を得た。
質量：(ES+) C₂₉H₃₁F₄N₇ 計算値 553.26; 実測値 554.2 [M+H], HPLC/MS 方法４。 Free base of compound 540-F, 2- [3- (4-trifluoromethylpyrimidine-2-ylamino) phenylamino] -3-fluoro-4- (4-tert-butylaminopiperidine-1-yl) quinoline hydrochloride Salt synthesis

A solution of compound 540-FI-1 (100 mg, 0.230 mmol) in NMP (2 ml) followed by 4- (tert-butylamino) piperidine (108 mg, 0.692 mmol) followed by DiPEA (0.06 ml, 0. 345 mmol) was added, and the obtained mixed solution was stirred at 220 ° C. in microwaves for 5 hours. Next, the reaction mixture was cooled to room temperature, diluted with ice water and AcOEt, and the aqueous layer was extracted with AcOEt. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give an off-white solid. The obtained solid was purified by flash chromatography (silicaline: 100-200 mesh, MeOH-DCM; 05:95 → 10:90) to 2- [3- (4-trifluoromethylpyrimidine-2-ylamino). ) Phenylamino] -3-fluoro-4- (4-tert-butylaminopiperidine-1-yl) quinoline, 0.4 g (31% yield) of off-white solid was obtained.
Mass: (ES +) C ₂₉ H ₃₁ F ₄ N ₇ Calculated 553.26; Measured 554.2 [M + H], HPLC / MS Method 4.

ＤＣＭ（２ｍｌ）中の化合物５４０−Ｆの遊離塩基（４０ｍｇ、０．０７２ｍｍｏｌ）の溶液に、エタノール（２．０ｍｌ）中の２Ｍ ＨＣｌを加え、混合液を室温で３０分間撹拌した。反応混合液を減圧下で濃縮し、ジエチルエーテルで洗浄して、２−［３−（４−トリフルオロメチルピリミジン−２−イルアミノ）フェニルアミノ］−３−フルオロ−４−（４−ｔｅｒｔ−ブチルアミノピペリジン−１−イル）キノリン塩酸塩に対応する４０ｍｇ（収率９５％）の黄色固体を得た。
質量：(ES+) C₂₉H₃₂ClF₄N₇ 計算値 553.26; 実測値 554.3 [M-HCl+H], HPLC/MS 方法４。 Synthesis of Compounds 540-F, 2- [3- (4-trifluoromethylpyrimidine-2-ylamino) phenylamino] -3-fluoro-4- (4-tert-butylaminopiperidine-1-yl) quinoline hydrochloride

2M HCl in ethanol (2.0 ml) was added to a solution of the free base (40 mg, 0.072 mmol) of compound 540-F in DCM (2 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture is concentrated under reduced pressure, washed with diethyl ether and 2- [3- (4-trifluoromethylpyrimidine-2-ylamino) phenylamino] -3-fluoro-4- (4-tert-butyl). A 40 mg (95% yield) yellow solid corresponding to aminopiperidin-1-yl) quinoline hydrochloride was obtained.
Mass: (ES +) C ₂₉ H ₃₂ ClF ₄ N ₇ Calculated value 553.26; Measured value 554.3 [M-HCl + H], HPLC / MS Method 4.

［ここで、Ｑ_１、Ｑ_２、Ｑ_３、びＱ_４は、それぞれ独立して、Ｈ、置換もしくは非置換アルキル、又は置換もしくは非置換アルコキシである］。 Additional examples of chemical synthesis
General procedure GP-1
This general procedure GP-1 can be used to prepare specific compounds of formula III, in particular compounds of formula III'-a below:

[Here, Q ₁ , Q ₂ , Q ₃ , and Q ₄ are H, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy, respectively].

［ここで、Ｑ_１、Ｑ_２、Ｑ_３、及びＱ_４は、それぞれ独立して、一般式ＩＩＩ’−ａで上に定義した通りである］。
ＤＭＦ中のイソシアアン酸アリール（１）（１．０ｍｍｏｌ）の窒素ガス下の溶液に、２−シアノ酢酸エチル（２）（１．２ｍｍｏｌ）を加え、続いてＥｔ_３Ｎ（２．５ｍｍｏｌ）を加えた。反応混合液を室温で３時間撹拌した。次に、反応混合液を砕いた氷水に注ぎ、濾過し、ｎ−ペンタンで洗浄して、２−シアノ−３−オキソ−３−（アリールアミノ）プロパン酸エチル（３）に対応する固体生成物を５０〜６５％の収率で得た。 Synthesis of ethyl 2-cyano-3-oxo-3- (arylamino) propanoate (3)

[Here, Q ₁ , Q ₂ , Q ₃ and Q ₄ are independently defined above in the general formula III'-a].
To a solution under nitrogen of Isoshiaan acid aryl (1) (1.0 mmol) in DMF, 2-cyanoethyl acetate (2) (1.2 mmol) was added, followed by _Et 3 N a (2.5 mmol) was added rice field. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture is then poured into crushed ice water, filtered, washed with n-pentane and the solid product corresponding to ethyl 2-cyano-3-oxo-3- (arylamino) propanoate (3). Was obtained in a yield of 50-65%.

［ここで、Ｑ_１、Ｑ_２、Ｑ_３、及びＱ_４は、それぞれ独立して、一般式ＩＩＩ’−ａで上に定義した通りである］。
１，２−ジクロロベンゼン中の２−シアノ−３−オキソ−３−（アリールアミノ）プロパン酸エチル（３）（１．０ｍｍｏｌ）の窒素ガス下の溶液を、１８５〜１９０℃で６時間加熱した。次に、反応混合液を室温に冷却し、濾過し、ＥｔＯＨで洗浄して、所望の化合物（４）（２，４−ジオキソ−１，２，３，４−テトラヒドロキノリン−３−カルボニトリル）（４）に対応する固体化合物を、少なくとも７０％（例えば、７２〜８５％）の収率で得た。 Synthesis of 2,4-dioxo-1,2,3,4-tetrahydroquinoline-3-carbonitrile derivative (4)

[Here, Q ₁ , Q ₂ , Q ₃ and Q ₄ are independently defined above in the general formula III'-a].
A solution of ethyl 2-cyano-3-oxo-3- (arylamino) propanoate (3) (1.0 mmol) in 1,2-dichlorobenzene under nitrogen gas was heated at 185-190 ° C. for 6 hours. .. The reaction mixture is then cooled to room temperature, filtered, washed with EtOH and the desired compound (4) (2,4-dioxo-1,2,3,4-tetrahydroquinoline-3-carbonitrile). The solid compound corresponding to (4) was obtained in a yield of at least 70% (eg, 72-85%).

［ここで、Ｑ_１、Ｑ_２、Ｑ_３、及びＱ_４は、それぞれ独立して、一般式ＩＩＩ’−ａで上に定義した通りである］。
ＰＯＣｌ_３中の２，４−ジオキソ−１，２，３，４−テトラヒドロキノリン−３−カルボニトリル誘導体（４）（１．０ｍｍｏｌ）の窒素ガス下の撹拌溶液に、ＰＣｌ_５（０．８０ｇ、０．７ｍｍｏｌ）を窒素雰囲気下で加え、６時間加熱還流した。次に、反応混合液を室温に冷却し、次に減圧下で溶媒を留去して残留物を得た。得られた残留物を冷水（１５℃未満）で粉砕し、濾過し、ｎ−ペンタンで洗浄して、化合物（５）（２，４−ジクロロ−キノリン−３−カルボニトリル誘導体）を淡黄色固体として少なくとも５０％（例えば、５７〜６９％）の収率で得た。 Synthesis of 2,4-dichloro-quinoline-3-carbonitrile derivative (5)

[Here, Q ₁ , Q ₂ , Q ₃ and Q ₄ are independently defined above in the general formula III'-a].
In a stirred solution of 2,4-dioxo-1,2,3,4-tetrahydroquinoline-3-carbonitrile derivative (4) (1.0 mmol) in _{POCl 3 under nitrogen gas, PCL 5} (0.80 g, 0.7 mmol) was added under a nitrogen atmosphere, and the mixture was heated under reflux for 6 hours. Next, the reaction mixture was cooled to room temperature, and then the solvent was distilled off under reduced pressure to obtain a residue. The resulting residue is ground in cold water (less than 15 ° C.), filtered and washed with n-pentane to give compound (5) (2,4-dichloro-quinoline-3-carbonitrile derivative) a pale yellow solid. Was obtained in yields of at least 50% (eg, 57-69%).

［ここで、Ｑ_１、Ｑ_２、Ｑ_３、及びＱ_４は、それぞれ独立して、一般式ＩＩＩ’−ａで上に定義した通りである］。
ＭｅＣＮ中の化合物（５）（２，４−ジクロロ−８−キノリン−３−カルボニトリル誘導体）（１．０ｍｍｏｌ）の窒素ガス下の攪拌溶液に、Ｎ−ｔｅｒｔ−ブチルピペリジン−４−アミン（６ａ）（１．２ｍｍｏｌ）を加えた。反応混合液を８０℃で４時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、ＭｅＣＮで洗浄して、化合物（７ａ）（２−クロロ−３−シアノ−４−［４−（ｔｅｒｔ−ブチルアミノ）ピペリジン−１−イル］キノリン誘導体）（固体生成物）を少なくとも５０％（例えば、５８〜７８％）の収率で得た。 Synthesis of 2-chloro-3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline derivative (7a):

[Here, Q ₁ , Q ₂ , Q ₃ and Q ₄ are independently defined above in the general formula III'-a].
N-tert-butylpiperidin-4-amine (6a) was added to a stirred solution of compound (5) (2,4-dichloro-8-quinoline-3-carbonitrile derivative) (1.0 mmol) in MeCN under nitrogen gas. ) (1.2 mmol) was added. The reaction mixture was stirred at 80 ° C. for 4 hours. The reaction mixture is then cooled to room temperature, filtered, washed with MeCN and compound (7a) (2-chloro-3-cyano-4- [4- (tert-butylamino) piperidine-1-yl). ] Quinoline derivative) (solid product) was obtained in yields of at least 50% (eg, 58-78%).

Synthesis of compound of formula III'-a (2- (4-chlorobenzylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline derivative)

Reaction under condition A (NMP, 85 ° C., 48 hours):
Stirring solution of compound (7a) (2-chloro-3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline derivative (1.0 mmol) in NMP (4 mL) under nitrogen gas. 4-Chlorobenzylamine (8) (4.0 mmol) was added to the mixture. The obtained mixture was stirred at 80 ° C. for 48 hours. Next, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between saline and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layer was _{dried with Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a solid residue. Is purified by preparative HPLC to obtain the desired compound (III'-a) (2- (4-chlorobenzylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl]. The quinoline derivative) was obtained as a solid product in a yield of at least 20%.

Reaction under Condition B (Pd (OAc) ₂ , xanthhos, t-BuONa, THF, 70 ° C., 5 hours) Compound 7a (2-chloro-4- [4- (tert-butylamino) piperidine-1) in THF. -Il] -3-Chlorobenzylamine (8) (1.3 mmol) and t-BuONa (3.0 mmol) were added to a stirred solution of (3-cyanoquinoline derivative) (1.0 mmol) under nitrogen gas. The obtained mixed solution was degassed with Ar gas for 30 minutes, then xantphos (0.1 mmol) and Pd (OAc) ₂ (0.1 mmol) were added, and the reaction mixed solution was stirred at 70 ° C. for 5 hours. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned between saline and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give the crude compound. The crude compound is purified by preparative HPLC and the corresponding compound formula of III'-a (2-chloro-3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] -quinoline derivative). Was obtained as a solid in a yield of at least 10%.

The compounds in the table below are prepared according to the general procedure GP-1:

［ここで、Ｒ^５及びＲ^６は、一般式ＩＩで定義した通りである］。 General procedure GP-2
The procedure GP-2 of the present invention can be used to prepare specific compounds of general formula II, in particular compounds of the following general formula II-a:

[Here, R ⁵ and R ⁶ are as defined by the general formula II].

［ここで、Ｒ^５及びＲ^６は、一般式ＩＩで定義した通りである］。 Synthesis of 3- or 4-substituted aminopiperidine derivative (6):

[Here, R ⁵ and R ⁶ are as defined by the general formula II].

Process A:
Acetic acid (0.1 mmol) in a stirring solution of 3- or 4-oxopiperidine-1-carboxylate tert-butyl (A) (1.0 mmol) and amine (B) (1.5 mmol) in DCE under nitrogen gas. ) Was added at 0 ° C. After 10 minutes, sodium triacetoxyborohydride (3.0 mmol) was added to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 16 hours. Next, the completion of the reaction was checked by TLC. Since TLC showed consumption of starting material, the reaction mixture was quenched with 1N NaOH aqueous solution and stirred at room temperature for 10 minutes. Next, the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material is then purified by column chromatography (silica gel (60-120 mesh), eluted with 0% -100% EtOAc in petroleum ether) to give at least 30 3- or 4-aminoBoc piperidine C. It was obtained in a yield of% (30-60%).

Process B:
A 4N HCl solution in dioxane (8 ml) was added to a stirred solution of 4 aminoBoc piperidine C (1.0 mmol) in DCM (5 ml) under nitrogen gas at 0 ° C. Next, the reaction mixture was stirred at room temperature for 3 hours. The completion of the reaction was then checked by TLC and the solvent was removed under reduced pressure as TLC showed consumption of the starting material. The resulting crude material was washed with diethyl ether and dried to yield compound (6b) (3- or 4-aminopiperidine) as a hydrochloride and as a solid compound at least 60% (eg 65-95%). Obtained at a rate.

［Ｒ^５及びＲ^６は、一般式ＩＩで定義した通りである］。
ＭｅＣＮ中の２，４−ジクロロ−３−シアノキノリン（５）（１．０ｍｍｏｌ）の窒素ガス下の溶液に、置換３−もしくは４−アミノピペリジン（６ｃ）（１．２ｍｍｏｌ）を加えた。反応混合液を８０℃で３時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、ＭｅＣＮで洗浄して、２−クロロ−３−シアノ−４−（３−もしくは４−置換アミノピペリジン−１−イル）キノリン（７ｂ）に対応する固体化合物を、少なくとも３０％（例えば、３５〜８７％）の収率で得た。 Synthesis of compound (7b) (2-chloro-3-cyano-4- (substituted 3- or 4-aminopiperidine-1-yl) quinoline):

[R ⁵ and R ⁶ are as defined in General Formula II].
Substituted 3- or 4-aminopiperidine (6c) (1.2 mmol) was added to a solution of 2,4-dichloro-3-cyanoquinoline (5) (1.0 mmol) in MeCN under nitrogen gas. The reaction mixture was stirred at 80 ° C. for 3 hours. The reaction mixture is then cooled to room temperature, filtered and washed with MeCN to 2-chloro-3-cyano-4- (3- or 4-substituted aminopiperidin-1-yl) quinoline (7b). The corresponding solid compound was obtained in yields of at least 30% (eg, 35-87%).

Note: TEA was used as a base in the reaction in the case of aminopiperidine (6c), which was used as the HCl salt (6b) to neutralize HCl in the reaction mixture.

ＴＨＦ（４ｍｌ）中の化合物（７ｂ）（２−クロロ−３−シアノ−４−（３−もしくは４−置換アミノピペリジン−１−イル）キノリン）（１．０ｍｍｏｌ）の窒素ガス下の攪拌溶液に、４−クロロベンジルアミン（８）（１．５ｍｍｏｌ）及びｔ−ＢｕＯＮａ（３．０ｍｍｏｌ）を加えた。得られた混合液をＡｒガスで１０分間脱気し、次にキサントホス（０．１ｍｍｏｌ）及びＰｄ（ＯＡｃ）_２（０．１ｍｍｏｌ）を加え、反応混合液を７０〜８０℃で５時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、減圧下で濃縮した。残留物を食塩水とＥｔＯＡｃに分配し、水層をＥｔＯＡｃで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、褐色固体を得た。後者をフラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＭｅＯＨ−ＤＣＭ；０％→１０％）又は分取ＨＰＬＣにより精製して、所望の式（ＩＩ−ａ）の化合物（２−（４−クロロベンジルアミノ）−３−シアノ−４−（３−もしくは４−置換アミノピペリジン−１−イル）キノリン）を、固体化合物として少なくとも５％（例えば６〜５０％）の収率で得た。 Synthesis of compound of formula II-a (2- (4-chlorobenzylamino) -3-cyano-4- (3- or 4-substituted aminopiperidin-1-yl) quinoline):

In a stirred solution of compound (7b) (2-chloro-3-cyano-4- (3- or 4-substituted aminopiperidin-1-yl) quinoline) (1.0 mmol) in THF (4 ml) under nitrogen gas. , 4-Chlorobenzylamine (8) (1.5 mmol) and t-BuONa (3.0 mmol) were added. The obtained mixed solution was degassed with Ar gas for 10 minutes, then xantphos (0.1 mmol) and Pd (OAc) ₂ (0.1 mmol) were added, and the reaction mixed solution was stirred at 70 to 80 ° C. for 5 hours. .. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned between saline and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown solid. The latter is purified by flash chromatography (silica gel: 100-200 mesh, MeOH-DCM; 0% → 10%) or preparative HPLC to give the compound of the desired formula (II-a) (2- (4-chlorobenzyl). Amino) -3-cyano-4- (3- or 4-substituted aminopiperidine-1-yl) quinoline) was obtained as a solid compound in a yield of at least 5% (eg 6-50%).

Note: In some instances the compounds 6c, the radicals R ⁵ and / or R ⁶ may be H. For these examples, the corresponding amine functional group (-NH ₂ or -NH-R ⁴ or -NH-R ⁵ ) is any suitable protecting group (eg, tertiary butoxycarbonyl (Boc), benzyloxycarbamate (eg, tertiary butoxycarbonyl (Boc)). It can be protected by Cbz) group). Therefore, the corresponding compound II-a will have an N-protected amine functional group on the piperidine ring. Conversion of these compounds II-a to the corresponding free base forms can be performed using any suitable deprotection technique known in the art.

The compounds in the table below are prepared according to the general procedure GP-2:

［ここで、Ｒ^５及びＲ^６は、一般式ＩＩで定義した通りである］。 General procedure GP-3
The procedure GP-3 of the present invention can be used to prepare specific compounds of general formula II, in particular compounds of the following general formula II-b:

[Here, R ⁵ and R ⁶ are as defined by the general formula II].

［Ｒ^５及びＲ^６は、一般式ＩＩ一般式ＩＩで定義した通りである］。 Synthesis of compound (6d) (3-substituted aminopyrrolidine derivative):

[R ⁵ and R ⁶ are as defined in General Formula II General Formula II].

Process A:
Acetic acid (0.1 mmol) was added to a stirring solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (1.0 mmol) and amine (B) (1.5 mmol) in DCE under nitrogen gas. Added at 0 ° C. After 10 minutes, sodium triacetoxyborohydride (3.0 mmol) was added to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 16 hours. Next, the completion of the reaction was checked by TLC, and since TLC showed consumption of the starting material, the reaction mixture was quenched with 1N NaOH aqueous solution, stirred at room temperature for 10 minutes, and then the aqueous layer was extracted with ethyl acetate. .. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material is then purified by column chromatography (silica gel (60-120 mesh), eluting 0-100% EtOAc in petroleum ether) to give at least 40 of the desired compound (C') (Boc-protected pyrrolidine). It was obtained in a yield of% (eg 43-77%).

Process B:
A 4N HCl solution (0 ° C.) in dioxane (8 ml) was added to a solution of compound (C') (Boc-protected pyrrolidine) (1.0 mmol) in DCM (5 ml) under nitrogen gas. Next, the reaction mixture was stirred at room temperature for 3 hours. The completion of the reaction was then checked by TLC and the solvent was removed under reduced pressure as TLC showed consumption of the starting material. The resulting crude material was washed with diethyl ether and then dried to give the desired compound (6d) (3-aminopyrrolidine derivative) as the hydrochloride and solid compound at least 80% (eg 85-90%). Was obtained in the yield of.

［Ｒ^５及びＲ^６は、一般式ＩＩで定義した通りである］。
ＭｅＣＮ（５ｍｌ）中の２，４−ジクロロ−３−シアノキノリン（５）（１．０ｍｍｏｌ）の窒素ガス下の溶液に、化合物６ｅ（１．０ｍｍｏｌ）を加えた。反応混合液を８０℃で３時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、ＭｅＣＮで洗浄して、２−クロロ−３−シアノ−４−（３−アミノピロリジン−１−イル）キノリン誘導体に対応する固体化合物（７ｃ）を、少なくとも５０％（５９〜８９％）の収率が得た。 Synthesis of compound (7c) (2-chloro-3-cyano-4- (3-aminopyrrolidine-1-yl) quinoline derivative):

[R ⁵ and R ⁶ are as defined in General Formula II].
Compound 6e (1.0 mmol) was added to a solution of 2,4-dichloro-3-cyanoquinoline (5) (1.0 mmol) in MeCN (5 ml) under nitrogen gas. The reaction mixture was stirred at 80 ° C. for 3 hours. The reaction mixture is then cooled to room temperature, filtered, washed with MeCN and the solid compound corresponding to the 2-chloro-3-cyano-4- (3-aminopyrrolidine-1-yl) quinoline derivative (7c). ), A yield of at least 50% (59-89%) was obtained.

Note: Triethylamine (TEA) was used as a base in the case of the intermediate (6e) obtained in the hydrochloride form (6d) to neutralize the HCl in the reaction mixture.

［Ｒ^５及びＲ^６は、一般式ＩＩで定義した通りである］。
ＴＨＦ（４ｍｌ）中の化合物（７ｃ）（２−クロロ−３−シアノ−４−（３−アミノピロリジン−１−イル）キノリン誘導体）（１．０ｍｍｏｌ）の窒素ガス下の溶液に、４−クロロベンジルアミン（８）（１．５ｍｍｏｌ）及びｔ−ＢｕＯＮａ（３．０ｍｍｏｌ）を加えた。得られた混合液をＡｒガスで１０分間脱気し、次にキサントホス（０．１ｍｍｏｌ）及びＰｄ（ＯＡｃ）_２（０．１ｍｍｏｌ）を加え、反応混合液を８０℃で５時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、減圧下で濃縮した。残留物を食塩水とＥｔＯＡｃに分配し、水層をＥｔＯＡｃで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して褐色固体を得た。粗化合物をフラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＭｅＯＨ−ＤＣＭ；０％→１０％）又は分取ＨＰＬＣにより精製して、式ＩＩ−ｂの化合物［２−（４−クロロベンジルアミノ）−３−シアノ−４−（３−アミノピロリジン−１−イル）キノリン誘導体］を、固体化合物として少なくとも５％（例えば６〜３２％）の収率で得た。 Compound of formula (II-b): Synthesis of 2- (4-chlorobenzylamino) -3-cyano-4- (3-aminopyrrolidine-1-yl) quinoline derivative:

[R ⁵ and R ⁶ are as defined in General Formula II].
4-Chloro in a solution of compound (7c) (2-chloro-3-cyano-4- (3-aminopyrrolidine-1-yl) quinoline derivative) (1.0 mmol) in THF (4 ml) under nitrogen gas. Benzylamine (8) (1.5 mmol) and t-BuONa (3.0 mmol) were added. The obtained mixed solution was degassed with Ar gas for 10 minutes, then xantphos (0.1 mmol) and Pd (OAc) ₂ (0.1 mmol) were added, and the reaction mixed solution was stirred at 80 ° C. for 5 hours. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned between saline and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown solid. The crude compound is purified by flash chromatography (silica gel: 100-200 mesh, MeOH-DCM; 0% → 10%) or preparative HPLC to formulate the compound of formula II-b [2- (4-chlorobenzylamino)-. 3-Cyano-4- (3-aminopyrrolidine-1-yl) quinoline derivative] was obtained as a solid compound in a yield of at least 5% (for example, 6 to 32%).

Note: In some instances the compounds 6e, the radicals R ⁵ and / or R ⁶ may be H. For these examples, the corresponding amine functional group (-NH ₂ or -NH-R ⁴ or -NH-R ⁵ ) is any suitable protecting group (eg, tertiary butoxycarbonyl (Boc), benzyloxycarbamate (eg, tertiary butoxycarbonyl (Boc)). It can be protected by Cbz) group). Therefore, the corresponding compound II-b will have an N-protected amine functional group on the pyrrolidine ring. Conversion of these compounds II-b to the corresponding free base form can be performed using any suitable deprotection technique known in the art.

The compounds in the table below are prepared according to the general procedure GP-3:

［ここで、Ｌ^２は単結合であり、Ｒ^２は置換もしくは非置換アリールオキシ、又は置換もしくは非置換ヘテロアリールオキシである］。 General procedure GP-4
The procedure GP-4 of the present invention can be used to prepare specific compounds of general formula II, in particular compounds of the following general formula II-c:

[Here, L ² is a single bond and R ² is a substituted or unsubstituted aryloxy, or a substituted or unsubstituted heteroaryloxy].

［ここで、Ｒ−Ｏ（＝Ｒ^２）は、置換もしくは非置換アリールオキシ、又は置換もしくは非置換ヘテロアリールオキシである］。 Synthesis of intermediate 6e:

[Here, RO (= R ² ) is a substituted or unsubstituted aryloxy, or a substituted or unsubstituted heteroaryloxy].

Process A:
DIAD (1.) In a solution of compound A "(3- or 4-Boc piperidinol) (1.0 mmol) in THF (20 ml) and aryl hydroxyl or heteroaryl hydroxyl (D) (1.0 mmol) under nitrogen gas. 1 mmol) and triphenylphosphine (1.1 mmol) were added at 0 ° C. The reaction mixture was stirred overnight at room temperature, then the completion of the reaction was checked by TLC and TLC showed consumption of starting material. The reaction mixture was quenched with 1N NaOH aqueous solution and stirred at room temperature for 10 minutes. Next, the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saline, dried with sodium sulfate, and filtered. The crude material was then purified by column chromatography (silica (60-120 mesh), eluted with 0% -100% EtOAc in petroleum ether) and Intermediate E (3-or 4-aryloxy or 3- or 4-heteroaryloxy Boc-piperidin) was obtained in yields of at least 30% (eg, 38-75%).

Process B:
4N in dioxane (8 mL) in a solution of intermediate E (3- or 4-aryloxy or 3- or 4-heteroaryloxy Boc-piperidine) (1.0 mmol) in DCM (5 ml) under nitrogen gas. The HCl solution was added to the mixture at 0 ° C. Next, the reaction mixture was stirred at room temperature for 3 hours. The completion of the reaction was then checked by TLC and the solvent was removed under reduced pressure as TLC showed consumption of the starting material. The resulting crude material is washed with diethyl ether, dried under vacuum and the desired intermediate (6e) (3- or 4-aryloxy or 3- or 4-heteroaryloxypiperidin derivative) is hydrochloride. And as a solid compound, obtained in yields of at least 50% (60-100%).

［ここで、Ｒ−Ｏ（＝Ｒ^２）は、置換もしくは非置換アリールオキシ、又は置換もしくは非置換ヘテロアリールオキシである］。
ＭｅＣＮ中の２，４−ジクロロ−３−シアノキノリン（５）（１．０ｍｍｏｌ）の窒素ガス下の溶液に、中間体（６ｆ）（３−もしくは４−アリールオキシ又は３−，４−ヘテロアリールオキシピペリジン誘導体）（１．５ｍｍｏｌ）を加えた。反応混合液を７０〜８０℃で３時間攪拌した。次に、反応混合液を室温に冷却し、濾過し、ＭｅＣＮで洗浄して、所望の中間体（７ｄ）（２−クロロ−３−シアノ−４−（３−もしくは４−アリールオキシ／ヘテロアリールオキシピペリジン−１−イル）キノリン誘導体）を、固体化合物として少なくとも４５％（例えば５１〜７８％）の収率で得た。 Synthesis of intermediate 7d:

[Here, RO (= R ² ) is a substituted or unsubstituted aryloxy, or a substituted or unsubstituted heteroaryloxy].
Intermediate (6f) (3- or 4-aryloxy or 3-,4-heteroaryl) in a solution of 2,4-dichloro-3-cyanoquinoline (5) (1.0 mmol) in MeCN under nitrogen gas. Oxypiperidine derivative) (1.5 mmol) was added. The reaction mixture was stirred at 70-80 ° C. for 3 hours. The reaction mixture is then cooled to room temperature, filtered, washed with MeCN and the desired intermediate (7d) (2-chloro-3-cyano-4- (3- or 4-aryloxy / heteroaryl)). Oxypiperidine-1-yl) quinoline derivative) was obtained as a solid compound in a yield of at least 45% (eg 51-78%).

Note: TEA was used as a base in the case of compound (6f) used in salt form (6e) to neutralize HCl from the reaction mixture.

［ここで、Ｒ−Ｏ（＝Ｒ^２）は、置換もしくは非置換アリールオキシ、又は置換もしくは非置換ヘテロアリールオキシである］。
ＴＨＦ（４ｍｌ）中の化合物（７ｄ）（２−クロロ−３−シアノ−４−（３−もしくは４−アリールオキシ／ヘテロアリールオキシピペリジン−１−イル）キノリン誘導体）（１．０ｍｍｏｌ）の窒素ガス下の溶液に、４−クロロベンジルアミン（８）（１．５ｍｍｏｌ）及びｔ−ＢｕＯＮａ（３．０ｍｍｏｌ）を加えた。得られた混合液をＡｒガスで１０分間脱気し、次にキサントホス（０．１ｍｍｏｌ）及びＰｄ（ＯＡｃ）_２（０．１ｍｍｏｌ）を加え、反応混合液を還流下で５時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、減圧下で濃縮した。残留物を食塩水とＥｔＯＡｃに分配し、水層をＥｔＯＡｃで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、褐色固体を得た。
各粗化合物を、フラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＭｅＯＨ−ＤＣＭ；０％→１０％）又は分取ＨＰＬＣにより精製して、対応する式ＩＩ−ｃの所望の化合物［２−（４−クロロベンジルアミノ）−３−シアノ−４−（３−もしくは４−アリールオキシ−ピペリジン−１−イル）キノリン、又は２−（４−クロロベンジルアミノ）−３−シアノ−４−（３−もしくは４−ヘテロアリールオキシ−ピペリジン−１−イル）キノリン］を、固体化合物として少なくとも９％（例えば９％〜３８％）の収率で得た。 Compound of formula II-c [2- (4-chlorobenzylamino) -3-cyano-4- (3- or 4-aryloxy-piperidine-1-yl) quinoline, or 2- (4-chlorobenzylamino) Synthesis of -3-cyano-4- (3- or 4-heteroaryloxy-piperidine-1-yl) quinoline]:

[Here, RO (= R ² ) is a substituted or unsubstituted aryloxy, or a substituted or unsubstituted heteroaryloxy].
Nitrogen gas of compound (7d) (2-chloro-3-cyano-4- (3- or 4-aryloxy / heteroaryloxypiperidine-1-yl) quinoline derivative) (1.0 mmol) in THF (4 ml) To the solution below was added 4-chlorobenzylamine (8) (1.5 mmol) and t-BuONa (3.0 mmol). The obtained mixture was degassed with Ar gas for 10 minutes, then xantphos (0.1 mmol) and Pd (OAc) ₂ (0.1 mmol) were added, and the reaction mixture was stirred under reflux for 5 hours. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned between saline and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown solid.
Each crude compound is purified by flash chromatography (silicaline: 100-200 mesh, MeOH-DCM; 0% → 10%) or preparative HPLC to the corresponding desired compound of formula II-c [2- (4). -Chlorobenzylamino) -3-cyano-4- (3- or 4-aryloxy-piperidine-1-yl) quinoline, or 2- (4-chlorobenzylamino) -3-cyano-4- (3- or 4-Heteroaryloxy-piperidine-1-yl) quinoline] was obtained as a solid compound in a yield of at least 9% (eg, 9% to 38%).

The compounds in the table below are prepared according to the general procedure GP-4:

［ここで：
Ｌ^１は単結合であり、
Ｒ^１は、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリール、置換もしくは非置換アリーレン、又は置換もしくは非置換ヘテロアリーレンであり、
Ｗは、Ｈ、ハロ、置換もしくは非置換アルキル、置換もしくは非置換アルコキシ、置換もしくは非置換アリールオキシ、置換もしくは非置換ヘテロアリールオキシ、置換もしくは非置換アリールアミノ、又は置換もしくは非置換ヘテロアリールアミノである］。

General procedure GP-5
The general procedure GP-5 of the present invention can be used to prepare specific compounds of general formula IV, in particular compounds of the following general formula IV-a:

[here:
L ¹ is a single bond
R ¹ is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene.
W is H, halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted arylamino, or substituted or unsubstituted heteroarylamino. be].

Reaction under condition A:
In a solution of 2-chloro-3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline 7a (1.0 mmol) in THF under nitrogen gas, the amine compound 10 (arylamine or Heteroarylamine) (1.5 mmol) and t-BuONa (3.0 mmol) were added. The obtained mixed solution was degassed with Ar gas for 30 minutes, then xantphos (0.1 mmol) and Pd (OAc) ₂ (0.1 mmol) were added, and the reaction mixed solution was stirred at 80 ° C. for 3 to 5 hours. .. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned between saline and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown solid.
The crude compound is purified by flash chromatography (silicaline: 230-400 mesh, MeOH-DCM; 0% → 10%) or preparative HPLC and the corresponding compound of the desired formula IV-a (2-substituted arylamino). -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline or 2-substituted heteroarylamino-3-cyano-4- [4- (tert-butylamino) piperidine-1 -Il] quinoline) was obtained as a solid compound in a yield of at least 5% (eg 5 to 43%).

Reaction under condition B:
In a solution of compound 7a (2-chloro-3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline) (1.0 mmol) in dioxane under nitrogen gas, the amine compound 10 ( Aryl- or heteroarylamine) (1.5 mmol) and Cs ₂ CO ₃ (3.0 mmol) were added. The resulting mixture is degassed with Ar gas for 30 minutes, then xantphos (0.1 mmol) and Pd ₂ (dba) ₃ (0.05 mmol) are added, and the reaction mixture is stirred under reflux for 3-5 hours. bottom. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned between saline and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown solid. The crude compound is purified by flash chromatography (silicaline: 230-400 mesh, MeOH-DCM; 0% → 10%) or preparative HPLC and the corresponding compound of the desired formula IV-a (2-substituted arylamino). -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline or 2-substituted heteroarylamino-3-cyano-4- [4- (tert-butylamino) piperidine-1 -Il] quinoline) was obtained as a solid compound in a yield of at least 20% (25-30%).

The compounds in the table below are prepared according to the general procedure GP-5:

［ここで：
Ｌ^１は置換もしくは非置換アルキレン、置換もしくは非置換アルケニレン、又は置換もしくは非置換アルキニレンであり；Ｒ^１は、置換もしくは非置換アリール、又は置換もしくは非置換ヘテロアリールであり；ＷはＨである］。 General procedure GP-6
The following procedure GP-6 can be used to prepare specific compounds of formula IV, in particular compounds of formula IV-b below:

[here:
L ¹ is a substituted or unsubstituted alkylene, a substituted or unsubstituted alkenylene, or a substituted or unsubstituted alkynylene; R ¹ is a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; W is H]. ..

［ここで、Ｌ^１、Ｒ^１、及びＷは、式ＶＩ−ｂで定義されるものである］。
Ｌ^１がメチレンである化合物の例：
ＴＨＦ（４ｍｌ）中の２−クロロ−３−シアノ−４−［４−（ｔｅｒｔ−ブチルアミノ）ピペリジン−１−イル］キノリン７ｅ（１．０ｍｍｏｌ）の窒素ガス下の溶液に、アリールメチルアミン又はヘテロアリールメチルアミン９（１．５ｍｍｏｌ）及びｔ−ＢｕＯＮａ（３．０ｍｍｏｌ）を加えた。得られた混合液をＡｒガスで３０分間脱気し、次にキサントホス（０．１ｍｍｏｌ）及びＰｄ（ＯＡｃ）_２（０．１ｍｍｏｌ）を加え、反応混合液を８０℃で５時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、減圧下で濃縮した。残留物を食塩水とＥｔＯＡｃに分配し、水層をＥｔＯＡｃで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、褐色固体を得た。
粗化合物をフラッシュクロマトグラフィー（シリカゲル：２３０〜４００メッシュ、ＭｅＯＨ−ＤＣＭ；０％→１０％）又は分取ＨＰＬＣにより精製して、対応する所望の式ＩＶ−ｂの化合物（２−置換アリールメチルアミノ−３−シアノ−４−［４−（ｔｅｒｔ−ブチルアミノ）ピペリジン−１−イル］キノリン、又は２−置換ヘテロアリールメチルアミノ−３−シアノ−４−［４−（ｔｅｒｔ−ブチルアミノ）ピペリジン−１−イル］キノリンを、固体化合物として少なくとも５％（例えば７〜２５％）の収率で得た。 Synthesis of compound of formula IV-b (2-substituted amino-3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline derivative):

[Here, L ¹ , R ¹ , and W are defined by the equation VI-b].
Examples of compounds where L ^{1 is methylene:}
Arylmethylamine or arylmethylamine or a solution of 2-chloro-3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline 7e (1.0 mmol) in THF (4 ml) under nitrogen gas. Heteroarylmethylamine 9 (1.5 mmol) and t-BuONa (3.0 mmol) were added. The obtained mixed solution was degassed with Ar gas for 30 minutes, then xantphos (0.1 mmol) and Pd (OAc) ₂ (0.1 mmol) were added, and the reaction mixed solution was stirred at 80 ° C. for 5 hours. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned between saline and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown solid.
The crude compound is purified by flash chromatography (silicaline: 230-400 mesh, MeOH-DCM; 0% → 10%) or preparative HPLC and the corresponding compound of the desired formula IV-b (2-substituted arylmethylamino). -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline, or 2-substituted heteroarylmethylamino-3-cyano-4- [4- (tert-butylamino) piperidine- 1-Il] quinoline was obtained as a solid compound in yields of at least 5% (eg 7-25%).

The compounds in the table below are prepared according to the general procedure GP-6:

［ここで、Ｌ^２は単結合であり、Ｒ^２は置換もしくは非置換アリールオキシ、又は置換もしくは非置換ヘテロアリールオキシである］。 General procedure GP-7:
The following procedure GP-7 can be used to prepare specific compounds of formula II, in particular compounds of formula II-d below:

[Here, L ² is a single bond and R ² is a substituted or unsubstituted aryloxy, or a substituted or unsubstituted heteroaryloxy].

［ここで、Ｒ−Ｏ（＝Ｒ^２）は、置換もしくは非置換アリールオキシ、又は置換もしくは非置換ヘテロアリールオキシである］。 Synthesis of compound 6h (3-aryloxy / heteroaryloxypyrrolidine HCl salt):

[Here, RO (= R ² ) is a substituted or unsubstituted aryloxy, or a substituted or unsubstituted heteroaryloxy].

Process A:
DIAD (1.1 mmol) in a solution of N-Boc pyrrolidine-3-ol A'''(1.0 mmol) and hydroxylaryl or hydroxylheteroaryl D (1.0 mmol) in THF (20 ml) under nitrogen gas. And triphenylphosphine (1.1 mmol) were added at 0 ° C. The reaction mixture was then stirred at room temperature overnight. Next, the completion of the reaction was checked by TLC, and since TLC showed consumption of the starting material, the reaction mixture was quenched with 1N NaOH aqueous solution and stirred at room temperature for 10 minutes. Next, the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material is then purified by column chromatography (silica gel (60-120 mesh), eluted with 0% -100% EtOAc in petroleum ether) and compound F (N-Boc3-aryloxy / heteroaryloxypyrrolidine). ) Was obtained in a yield of at least 20% (eg, 25-67%).

Process B:
To a solution of compound F (N-Boc3-aryloxy / heteroaryloxypyrrolidine) (1.0 mmol) in DCM (5 ml) under nitrogen gas was added a 4N HCl solution in dioxane (4 ml) at 0 ° C. Next, the reaction mixture was stirred at room temperature for 3 hours. The completion of the reaction was then checked by TLC and the solvent was removed under reduced pressure as TLC showed consumption of the starting material. The resulting crude material is washed with diethyl ether and dried to yield compound 6h (3-aryloxy / heteroaryloxypyrrolidine) in the form of hydrochloride at least 70% (eg 81-95%) as a solid compound. Obtained at a rate.

［ここで、Ｒ−Ｏ（＝Ｒ^２）は、置換もしくは非置換アリールオキシ、又は置換もしくは非置換ヘテロアリールオキシである］。
ＭｅＣＮ中の２，４−ジクロロ−３−シアノキノリン５（１．０ｍｍｏｌ）の窒素ガス下の溶液に、アミン化合物６ｉ（３−アリールオキシもしくは３−ヘテロアリールオキシピロリジン）（１．０ｍｍｏｌ）を加えた。反応混合液を８０℃で３時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、ＭｅＣＮで洗浄して、中間体７ｅ（２−クロロ−３−シアノ−４−（３−アリールオキシもしくは３−ヘテロアリールオキシピロリジン−１−イル）キノリン）に対応する固体化合物を、少なくとも４０％（例えば４６〜８８％）の収率で得た。 Synthesis of Intermediate 7e (2-Chloro-3-cyano-4- (3-aryloxy or 3-heteroaryloxypyrrolidine-1-yl) quinoline):

[Here, RO (= R ² ) is a substituted or unsubstituted aryloxy, or a substituted or unsubstituted heteroaryloxy].
Amine compound 6i (3-aryloxy or 3-heteroaryloxypyrrolidine) (1.0 mmol) is added to a solution of 2,4-dichloro-3-cyanoquinoline 5 (1.0 mmol) in MeCN under nitrogen gas. rice field. The reaction mixture was stirred at 80 ° C. for 3 hours. The reaction mixture is then cooled to room temperature, filtered, washed with MeCN and intermediate 7e (2-chloro-3-cyano-4- (3-aryloxy or 3-heteroaryloxypyrrolidine-1-). The solid compound corresponding to i) quinoline) was obtained in yields of at least 40% (eg 46-88%).

Note: In the case of the amine compound 6i (3-aryloxy or 3-heteroaryloxypyrrolidine) used in the form of HCl salt 6h to neutralize HCl from the reaction mixture, TEA as the base used.

［ここで、Ｒ−Ｏ（＝Ｒ^２）は、置換もしくは非置換アリールオキシ、又は置換もしくは非置換ヘテロアリールオキシである］。
ＴＨＦ（４ｍｌ）中の中間体７ｅ（２−クロロ−３−シアノ−４−（３−アリールオキシ／ヘテロアリールオキシピロリジン−１−イル）キノリン）（１．０ｍｍｏｌ）の窒素ガス下の溶液に、４−クロロ−ベンジルアミン８（１．５ｍｍｏｌ）及びｔ−ＢｕＯＮａ（３．０ｍｍｏｌ）を加えた。得られた混合液をＡｒガスで１０分間脱気し、次にキサントホス（０．１ｍｍｏｌ）及びＰｄ（ＯＡｃ）_２（０．１ｍｍｏｌ）を加え、反応混合液を還流下で３〜５時間撹拌した。次に、反応混合液を室温に冷却し、濾過し、減圧下で濃縮した。残留物を食塩水とＥｔＯＡｃに分配し、水層をＥｔＯＡｃで抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、褐色固体を得た。粗化合物をフラッシュクロマトグラフィー（シリカゲル：１００〜２００メッシュ、ＭｅＯＨ−ＤＣＭ：０％→１０％）により精製して、化合物ＩＩ−ｄ（２−（４−クロロベンジルアミノ）−３−シアノ−４−（３−アリールオキシ又は３−ヘテロアリールオキシピロリジン−１−イル）キノリン）を固体化合物として、少なくとも３％（例えば３〜４１％）の収率で得た。 Synthesis of compound of formula II-d (2- (4-chlorobenzylamino) -3-cyano-4- (3-aryloxy or 3-heteroaryloxypyrrolidine-1-yl) quinoline):

[Here, RO (= R ² ) is a substituted or unsubstituted aryloxy, or a substituted or unsubstituted heteroaryloxy].
In a solution of intermediate 7e (2-chloro-3-cyano-4- (3-aryloxy / heteroaryloxypyrrolidine-1-yl) quinoline) (1.0 mmol) in THF (4 ml) under nitrogen gas, 4-Chloro-benzylamine 8 (1.5 mmol) and t-BuONa (3.0 mmol) were added. The obtained mixture was degassed with Ar gas for 10 minutes, then xantphos (0.1 mmol) and Pd (OAc) ₂ (0.1 mmol) were added, and the reaction mixture was stirred under reflux for 3 to 5 hours. .. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned between saline and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure to give a brown solid. The crude compound is purified by flash chromatography (silica gel: 100-200 mesh, MeOH-DCM: 0% → 10%) and compound II-d (2- (4-chlorobenzylamino) -3-cyano-4- (3-aryloxy or 3-heteroaryloxypyrrolidine-1-yl) quinoline) was obtained as a solid compound in a yield of at least 3% (for example, 3-41%).

The compounds in the table below are prepared according to the general procedure GP-7:

^＊使用されたＨＰＬＣ／ＭＳ分析方法、^ｂＲｔ：保持時間（分）、^ｃ使用されたＨＰＬＣ／ＵＶ分析方法、^ｄＮＭＲ ^１Ｈ法、^ｅＮＭＲ ^１３Ｃ法、^＃［Ｍ−２ ＨＣｌ］ＭＨ＋、ＩＲ又は ＮＭＲ欄の印「X」は 対応するデータが利用可能であることを意味する。 Analytical data

^* HPLC / MS analysis methods ^used, b Rt: retention time ^{(min), c} that was used HPLC / UV analytical ^method, d NMR ¹ H ^method, e ^{NMR 13} C ^{method, # [M-2 HCl]} MH +, The mark "X" in the IR or NMR column means that the corresponding data is available.

III. Biological Evaluation Example 5: Activity profile of the compounds of the invention in HepG2, Huh-7, HCT-116, A375, MOLM-14, 786-O cell lines.

Cell culture _{: All cell lines are cultured at 37 ° C., 5% CO 2} in medium containing 1% penicillin-streptomycin (Dutscher, P06-07100) and 10% fetal bovine serum (Hyclone Dutscher, RZK35922). Maintained. HepG2 (hepatocellular carcinoma) strains are cultured in Dulbecco's modified Eagle's medium low glucose (Gibco, 21885025), Huh7 (hepatocellular carcinoma), HCT-116 (colorectal cancer), PANC-1 (pancreatic cancer), and The A375 (malignant melanoma) cell line was cultured in Dulvecco's modified Eagle's medium (Dutscher, L0103). The MOLM-14 (acute myeloid leukemia) cell line was maintained in MEM alpha medium (Gibco, 22561-021). The 786-O (kidney adenocarcinoma) cell line was maintained in RPMI 1640 medium (Dutscher, L0498).

Cell Viability Assay : Cell viability is determined using the Infinite F200 Pro Illuminometer (Tecan) using the CellTiter-Glo® Luminescent Cell Viability Assay described by the manufacturer (Promega, Ref G7571). It was measured. Briefly, for adherent cells, cells were seeded on 96-well plates (with a white, transparent bottom) in 90 μL of medium per well and grown overnight prior to the assay. For cells growing in suspension, cells were seeded on 96-well plates 1 hour prior to assay. The number of seeded cells per well is shown in Table 8 below.

Compounds were resuspended in H _{2 O} or DMSO, was added at different concentrations to each well and the cell cultures were incubated for 72 hours. Use the diluent _{(H 2} O or DMSO) as a control, all compounds were tested at a constant rate of _{H 2} O or DMSO. On the day of reading, the plates were equilibrated at room temperature for 30 minutes, then 100 μL of CellTiter-Glo® was added and luminescence was measured using Infinite F200Pro (Tecan). % Cell viability was expressed as a percentage of the signal obtained for cell cultures treated with diluent. EC ₅₀ values were determined as the dose of compound required to reduce the emission value to 50% of the signal obtained for the treated cell cultures at a dilution agent. Experimental data were analyzed using a computer program, Graphpad Prism v5 (GraphPad Software, Inc., La Jolla, CA). All points were made at least in double measurements.

The following Table 9 and 9a are when tested against the following cancer cell lines, showing an _{EC 50} range of the measured compounds by the above method: respectively, MOLM-14; A375; HCT -116; Huh7; PANC -1; 786-O; HepG2.

The results are shown below:
A is, ≦ 10 [mu] M to> B representing an _{EC 50} value of 5μM range, ≦ 5μM~> C representing an _{EC 50} value in the range of 0.5μM are, ≦ 0.5 um to> range of 0.05μM of EC Represents _{50 values}

These results demonstrate the ability of the compounds of the invention to effectively inhibit the growth of various cancer cell lines.

Taken together, these data indicate that the compounds of the invention are useful as antiproliferative agents, especially as antineoplastic agents, and more specifically as anticancer agents, due to their ability to affect cell viability in various cancer cell lines. Prove that you have.

Claims (22)

A compound having a structure represented by the following formula (I):

[During the ceremony,
L ¹ is a single bond, or substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted alkynylene;
L ² is a single bond or carbonyl;
R ¹ is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
R ² is hydroxyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted alkoxycarbonylamino, substituted or unsubstituted aryloxycarbonylamino, substituted or unsubstituted heteroaryl. Oxycarbonylamino, substituted or unsubstituted alkylaminocarbonylamino, substituted or unsubstituted arylaminocarbonylamino, substituted or unsubstituted heteroarylaminocarbonylamino, or NR ⁵ R ⁶ (where each R ⁵ and R ⁶ are independent. H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl);
Q ₁ , Q ₂ , Q ₃ and Q ₄ are independently H, hydroxyl, halo, amino, nitro, thiol, carboxyl, cyano, azide, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted. Alternatively, unsubstituted alkynyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or non-substituted. Substituted alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted sulfanyl, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted arylamino, substituted or unsubstituted hetero Arylamino, substituted or unsubstituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted sulfo, substituted. Sulfonyl, substituted sulfinyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted sulfonylamino, substituted or unsubstituted aminocarbonylamino, substituted or unsubstituted aminocarbonyloxy, substituted or unsubstituted alkoxycarbonylamino, substituted or unsubstituted aryloxycarbonyl Amino, or substituted or unsubstituted heteroaryloxycarbonylamino;
R ^3a is halo, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkoxy, substituted or An unsubstituted alkoxycarbonyl, a substituted or unsubstituted aryloxycarbonyl, a substituted or unsubstituted heteroaryloxycarbonyl, or a substituted or unsubstituted aminocarbonyl;
Each R ^3b is independently H, hydroxyl, halo, azide, amino, nitro, thiol, cyano, carboxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted arylalkyl. , Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocycloalkyl;
R ^3c is H;
W is optionally present, and if present, H, hydroxyl, halo, azido, amino, nitro, thiol, cyano, carboxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted. Alternatively, unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkoxy, substituted or non-substituted. Substituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted sulfanyl, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted arylamino, substituted or unsubstituted heteroarylamino, substituted or non-substituted Substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted sulfo, substituted sulfonyl, substituted sulfinyl, substituted Alternatively, unsubstituted aminosulfonyl, substituted or unsubstituted sulfonylamino, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted aminocarbonylamino, substituted or unsubstituted aminocarbonyloxy, substituted or unsubstituted alkoxycarbonylamino. , Substituted or unsubstituted aryloxycarbonylamino, or substituted or unsubstituted heteroaryloxycarbonylamino;
m is 0, 1, 2, 3, or 4;
If m is 0, d is independently 0, 1, or 2; if m is 1, d is independently 0, 1, 2, or 3; if m is 2. , D independently are 0, 1, 2, 3, or 4; if m is 3, then d is independently 0, 1, 2, 3, 4, or 5, or m is 4 If d is independently 0, 1, 2, 3, 4, 5, or 6],
Or its pharmaceutically acceptable salts, hydrates, solvates, or its isotopes variants, tautomer, or stereoisomer thereof. The compound according to claim 1, wherein L ¹ is a single bond or a substituted or unsubstituted alkylene. The compound according to any one of claims 1 or 2, wherein m is 0, 1, or 2. The compound according to claim 1, wherein L ² is a single bond, R ² is NR ⁵ R ⁶ , and in the formula, R ⁵ and R ^{6 are as defined in claim 1.} The compound according to claim 1, wherein L ¹ is a substituted or unsubstituted alkylene, a substituted or unsubstituted alkenylene, or a substituted or unsubstituted alkynylene; R ¹ is a substituted or unsubstituted arylene; and W is a halo. .. The compound according to claim 1, wherein L ¹ is a single bond; R ¹ is a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene. The compound according to claim 1, wherein L ¹ is a single bond; R ¹ is a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; W is a substituted or unsubstituted heteroarylamino. R ¹ is substituted or unsubstituted phenylene-1,4-diyl, substituted or unsubstituted phenylene-1,3-diyl, or substituted or unsubstituted naphthalene-1,4; R ^3a is halo, cyano, substituted or The compound according to claim 1, which is an unsubstituted alkyl, or a substituted or unsubstituted alkoxycarbonyl. R ¹ is a substituted or unsubstituted pyridinediyl, substituted or unsubstituted pyrimidine-diyl, substituted or unsubstituted pyrazinediyl, substituted or unsubstituted 1H- Pirazorujiiru, oxazolediyl, or substituted or unsubstituted isoxazolediyl; R ^3a is , Halo, cyano, or substituted or unsubstituted C _{1 to} C ₆ alkyl, substituted or unsubstituted alkoxycarbonyl, the compound according to claim 1. W is pyrimidine-2-yl-amino, pyrimidine-4-yl-amino, pyrimidine-5-yl-amino, 1H-pyrazole-5-yl-amino, 1H-pyrazole-4-yl-amino, flo [2]. , 3-d] The compound according to claim 7, which is pyrimidine-2-yl-amino, pyridine-2-yl-amino, pyridine-3-yl-amino, or pyridine-4-yl-amino. The compound according to claim 1, which is selected from the group consisting of the following:
2- (4-Chlorobenzylamino) -3-fluoro-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-methyl-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
Methyl 4- (4- (tert-butylamino) piperidine-1-yl) -2- (4-chlorobenzylamino) quinoline-3-carboxylate,
2- [4- (4-Methylpyrimidine-2-ylamino) phenylamino] -3-methyl-4- (4-tert-butylaminopiperidine-1-yl) quinoline,
2- [3- (4-Trifluoromethylpyrimidine-2-ylamino) phenylamino] -3-methyl-4- (4-tert-butylaminopiperidine-1-yl) quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- [4- (4- (Pyridine-3-yl) pyrimidin-2-ylamino) -3-methylbenzylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline,
2- (3-Methyl-4- (4-methylpyrimidine-2-ylamino) phenylamino) -3-cyano-4- (4- (tert-butylamino) piperidine-1-yl) -quinoline,
2- [4- (4,6-dimethyl-2-pyrimidineamino) -3-methyl-phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline,
2- [4- (4-Methyl-6-Methoxypyrimidine-2-ylamino) -3-methylphenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline,
2- [3-Methyl-4- (4,6-dimethylflo [2,3-d] pyrimidin-2-ylamino) Phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) ) Quinoline,
2- {3-Methyl-4- [2- (pyridin-3-yl) pyrimidin-4-ylamino] phenylamino} -3-cyano-4- (4-tert-butylaminopiperidin-1-yl) quinoline,
2- {3-Methyl-4- [2- (pyridin-3-yl) -5-cyanopyrimidine-4-ylamino] phenylamino} -3-cyano-4- (4-tert-butylaminopiperidine-1-) Il) quinoline,
2- [4- (4-Methylpyrimidine-2-ylamino) phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline,
2- [3-Methyl-4- (4-trifluoromethylpyrimidine-2-ylamino) phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline,
2- [3- (4-Trifluoromethyl-2-pyrimidineamino) -4-methyl-phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline,
2- [3- (4-Trifluoromethylpyrimidine-2-ylamino) phenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline,
2- [4- (4- (Pyridine-3-yl) pyrimidin-2-ylamino) -3-methylphenylamino] -3-cyano-4- (4-tert-butylaminopiperidine-1-yl) quinoline,
2- [3- (4-Trifluoromethylpyrimidine-2-ylamino) phenylamino] -3-fluoro-4- (4-tert-butylaminopiperidine-1-yl) quinoline,
2- (4-Fluorobenzylamino) -3-fluoro-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (4-Fluorobenzylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] -8-methylquinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] -7-methylquinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] -6-methylquinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- (3-aminopiperidin-1-yl) quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (methylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (isopropylamino) piperidine-1-yl] quinoline,
{[(Tetrahydro-2H-pyra-4-yl) methyl] amino} -3-fluoro-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (cyclopentylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (dimethylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (diethylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- (4-aminopiperidine-1-yl) quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (methylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (isopropylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4-{4-[(tert-butyloxycarbonyl) amino] piperidine-1-yl} quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (cyclopentylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4-{4-[(tetrahydro-2H-pyran-4-yl) amino] piperidine-1-yl} quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4-{4-[(1-methylpiperidine-4-yl) amino] piperidine-1-yl} quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (dimethylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (diethylamino) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3-aminopyrrolidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (methylamino) pyrrolidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (cyclopentylamino) pyrrolidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4-{3-[(tetrahydro-2H-pyran-4-yl) amino] pyrrolidine-1-yl} quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (dimethylamino) pyrrolidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (diethylamino) pyrrolidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- (3-phenoxypiperidine-1-yl) quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (4-methoxyphenoxy) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (4-methylphenoxy) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (4-fluorophenoxy) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (3-fluorophenoxy) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4-{3-[(3-methylpyrazine-2-yl) oxy] piperidine-1-yl} quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- (4-phenoxypiperidine-1-yl) quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (4-methoxyphenoxy) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (p-tolyloxy) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (4-chlorophenoxy) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (4-fluorophenoxy) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [4- (3-fluorophenoxy) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4-{4-[(pyridin-4-yl) oxy] piperidine-1-yl} quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4-{4-[(5-methylisoxazole-3-yl) oxy] piperidine-1-yl} quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4-{4-[(3-methylpyrazine-2-yl) oxy] piperidine-1-yl} quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- (3-phenoxypyrrolidine-1-yl) quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (4-methylphenoxy) pyrrolidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (4-methoxyphenoxy) pyrrolidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (4-chlorophenoxy) pyrrolidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (4-fluorophenoxy) pyrrolidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4- [3- (3-fluorophenoxy) pyrrolidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4-{3-[(3-methylpyrazine-2-yl) oxy] pyrrolidine-1-yl} quinoline,
2- (4-Chlorobenzylamino) -3-cyano-4-{3-[(pyridin-4-yl) oxy] pyrrolidine-1-yl} quinoline,
2- (Phenylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (4-Methylphenylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (3-Methyl-4-fluorophenylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (4-Methoxyphenylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (2-Trifluoromethylphenylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (3-Trifluoromethylphenylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (4-Chlorophenylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (4-Fluorophenylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (3-Fluorophenylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (3,4-difluorophenylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- [4- (trifluoromethyloxy) phenylamino] -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2-[(1-Methyl-1H-pyrazole-4-yl) amino] -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2-[(1-Methyl-1H-1,2,4-triazole-5-yl) amino] -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2-[(1,3-dimethyl-1H-1,2,4-triazole-5-yl) amino] -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- {4- [(4,6-dimethylpyrimidine-2-yl) amino] phenylamino} -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (Pyridine-2-ylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (Pyrimidine-2-ylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (Pyrimidine-4-ylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (Pyrazine-2-ylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (Benzylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (4-Methylbenzylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- (4-Methoxybenzylamino) -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- [4- (Trifluoromethyl) benzylamino] -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2- [2- (Trifluoromethyl) benzylamino] -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2-[(Benzo [d] [1,3] dioxol-5-ylmethyl) amino] -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2-[(Fran-2-ylmethyl) amino] -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2-[(Pyridine-3-ylmethyl) amino] -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2-[(Pyridine-4-ylmethyl) amino] -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
2-[(Pyridine-2-ylmethyl) amino] -3-cyano-4- [4- (tert-butylamino) piperidine-1-yl] quinoline,
Or a pharmaceutically acceptable salt, hydrate, solvate, or its isotopes variants, tautomer, or stereoisomer thereof. The compound according to claim 1, which has a structure represented by the formula (II):

[During the ceremony,
L ² , R ² , R ^3a , R ^3b , R ^3c , and d and m are as defined in claim 1],.
Or its pharmaceutically acceptable salts, hydrates, solvates, or its isotopes variants, tautomer, or stereoisomer thereof. The compound according to claim 1, which has a structure represented by the formula (IV):

[In the formula, L ¹ , R ¹ , R ^3a , and W are as defined in claim 1.]
Or its pharmaceutically acceptable salts, hydrates, solvates, or its isotopes variants, tautomer, or stereoisomer thereof. R ^3a is a halo, cyano, or substituted or unsubstituted alkoxycarbonyl; L ¹ is a single-bonded, or substituted or unsubstituted alkylene; R ¹ is a substituted or unsubstituted aryl, or substituted or unsubstituted hetero. Aryl; W is a substituted or unsubstituted arylamino, or a substituted or unsubstituted heteroarylamino; the compound according to claim 13. Compounds selected from the following group:
(2S) 2- (4-chlorobenzylamino) -4- [2- (hydroxymethyl) pyrrolidine-1-yl] quinoline,
(2S) 2- (4-chlorobenzylamino) -4- [2- (methoxymethyl) pyrrolidine-1-yl] quinoline,
(2R) -2- (4-chlorobenzylamino) -4- [2- (hydroxymethyl) -pyrrolidin-1-yl] -quinoline,
2- (4-Chlorobenzylamino) -4- (4-hydroxypiperidine-1-yl) quinoline,
2- (4-Chlorobenzylamino) -4- [4- (iso-propoxy) -piperidine-1-yl] -quinoline,
2- (4-Chlorobenzylamino) -4- (4-phenoxypiperidine-1-yl) -quinoline,
2- (4-Chlorobenzylamino) -4- [4- (m-tolyloxy) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -4- [4- (pyridin-4-yloxy) piperidine-1-yl] quinoline,
2- (4-Chlorobenzylamino) -4- [4- (pyrazine-2-yloxy) piperidine-1-yl] quinoline,
(3R) 2- (4-chlorobenzylamino) -4- (3-hydroxypyrrolidin-1-yl) quinoline,
(3R) 2- (4-chlorobenzylamino) -4- [3- (phenoxy) pyrrolidine-1-yl] quinoline,
(3R) 2- (4-chlorobenzylamino) -4- [3- (pyridin-2-yloxy) pyrrolidine-1-yl] quinoline,
(3S) 2- (4-chlorobenzylamino) -4- (3-hydroxypyrrolidin-1-yl) -quinoline,
(3S) 2- (4-chlorobenzylamino) -4- [3- (pyridin-2-yloxy) pyrrolidine-1-yl] quinoline,
Or its pharmaceutically acceptable salts, hydrates, solvates, or its isotopes variants, tautomer, or stereoisomer thereof. a) The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, hydrate, solvate thereof, alone or in combination with at least one additional therapeutically active substance. things, or includes its isotope variants, tautomer, or stereoisomer thereof, a and b) one or more pharmaceutically acceptable carriers, pharmaceutical compositions. Use as a medicament A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, hydrate, solvate, or their isotopic variants, tautomeric A pharmaceutical composition comprising a body or a stereoisomer. The compound according to any one of claims 1 to 15, or a pharmaceutical agent used in the treatment, prevention, suppression or amelioration of a proliferative disease, alone or in combination with at least one additional therapeutically active substance. acceptable salts, hydrates, solvates, or their isotopic variants, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, pharmaceutical compositions. The pharmaceutical composition according to claim 18, wherein the proliferative disease is selected from neoplastic and non-neoplastic diseases. The neoplastic disease is cancer, and the cancer is malignant tumor, malignant lymphoma, malignant melanoma, malignant stellate cell tumor, benign tumor, solid tumor, sarcoma, cancer, cartinoid, Ewing sarcoma, capo sarcoma, brain tumor, brain. And / or nervous system and / or medullary-derived tumors, gliomas, gliomas, blastomas, gastric cancers, pancreatic cancers, kidney cancers, renal cell carcinomas, prostate cancers, prostate carcinomas, connective tissue tumors, Soft tissue sarcoma, fibrosarcoma, pancreatic tumor, liver cancer, head eye, cervical cancer, laryngeal cancer, nasopharyngeal cancer, esophageal cancer, colon cancer, thyroid cancer, osteosarcoma, retinal blastoma, thoracic adenoma, testicular cancer, Lung cancer, lung adenocarcinoma, small cell lung cancer, bronchial cancer, breast cancer, breast cancer (mamma carcinoma), intestinal cancer, colon-rectal tumor, colon cancer, prostate cancer, rectal cancer, gynecological tumor, ovarian tumor, uterus Cancer, cervical cancer, cervix carcinoma, uterine body cancer, corpus cancer, endometrial cancer, bladder cancer, urogenital tract cancer, bladder cancer, skin cancer, epithelial tumor, squamous epithelial cancer , Basilica cell cancer, basal cell tumor, myeloma, melanoma, intraocular melanoma, leukemia, monocytic leukemia, chronic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, acute leukemia, acute myeloid leukemia, acute premyelocytic leukemia (APL), acute lymphocytic leukemia, acute T lymphoblastic leukemia, adult T cell leukemia, basal leukemia, eosinophilic leukemia, granulocytic leukemia, hairy cell leukemia, leukocyte-depleting leukemia, lymph Consists of sex leukemia, lymphoblastic leukemia, lymphocytic leukemia, macronuclear leukemia, small bone marrow blastic leukemia, monocytic leukemia, neutrophil leukemia, stem cell leukemia, germ cell cancer, and metastatic proliferation The pharmaceutical composition according to claim 19, which is selected from the group. The pharmaceutical composition according to claim 20, wherein the liver cancer is selected from the group consisting of hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma. 13. one wherein the compound, or pharmaceutically acceptable salts, hydrates, solvates, or include their isotopic variants, tautomer, or a stereoisomer, pharmaceutical compositions.